tag:blogger.com,1999:blog-1812431336777691886.post3305291947302780024..comments2024-02-29T03:57:00.088-05:00Comments on The Mermaid's Tale: If I'm healthy, why should I have my genome sequenced?Anne Buchananhttp://www.blogger.com/profile/09212151396672651221noreply@blogger.comBlogger18125tag:blogger.com,1999:blog-1812431336777691886.post-85294812391775416782013-08-16T11:47:24.864-04:002013-08-16T11:47:24.864-04:00Thanks. Feel free to post comments and criticisms...Thanks. Feel free to post comments and criticisms here when you have them.Eric Turkheimerhttps://www.blogger.com/profile/07059094707929916121noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-6226876386945149582013-08-16T11:21:23.820-04:002013-08-16T11:21:23.820-04:00Thanks very much, Erik, and you are certainly forg...Thanks very much, Erik, and you are certainly forgiven for plugging your own paper, especially since it begins with a section titled "GWAS and Its Discontents"! I look forward to reading the whole thing.<br /><br />And, yep, concur with your model and conclusions. Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-42792696408411931682013-08-16T11:13:50.004-04:002013-08-16T11:13:50.004-04:00Hi, I wanted to let you know how happy I am to hav...Hi, I wanted to let you know how happy I am to have discovered this blog, and this seems to be as good an entry point as any. Although I have spent a lifetime thinking about the role of genetics in the genesis of complex human behavior and am currently the past-President of the Behavior Genetics Association, I often find myself in disagreement with my colleagues about reductionistic causal models in gene-behavior relations. <br /><br />If I can be forgiven for plugging one of my own papers here, you might be interested in:<br /><br />http://people.virginia.edu/~ent3c/papers2/Turkheimer%20GWAS%20EWAS%20Final.pdf<br /><br />Some other things I have written will be cited there.<br /><br />Here is my standard argument about the limitations of GWAS. Suppose you are given a stack of DVDs with movies on them, and a microscope. You are told to examine the pattern of dots or whatever through the microscope. Your task is to figure out on this basis whether the movie is a drama or a comedy.<br /><br />My conclusions:<br /><br />1) No one is denying that one way or another all the information about the movie is encoded on the DVD.<br /><br />2) Nevertheless, it won't work.<br /><br />3) Because the microscope does not encompass the developmental model via which the data on the disc gets turned into a movie.<br /><br />4) Sample size is not the issue.<br /><br />5) Despite everything, you will still get some hits. That is, if you have enough DVDs, sooner or later you would find some location on the disc whose state was correlated with drama v. comedy at some level of statistical significance.<br /><br />Anyway, thanks again for the blog.<br /><br />Eric TurkheimerEric Turkheimerhttps://www.blogger.com/profile/07059094707929916121noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-30521109230789753782013-08-07T07:14:43.917-04:002013-08-07T07:14:43.917-04:00Thanks very much for your thoughtful replies (and ...Thanks very much for your thoughtful replies (and your kind comments re. the blog!). I respect and appreciate your reasons for doing 23andMe. Of the reasons people have offered for doing sequencing, the one I most get is curiosity. And, yes, time will tell.Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-29037299895496284422013-08-07T07:10:22.448-04:002013-08-07T07:10:22.448-04:00There are just differences of view at play here. ...There are just differences of view at play here. If data were free to collect and made openly available (but confidentiality somehow preserved!), then clearly there will be things to find there, and some--the clear-cut risks--would be identified (as we've long had methods to do, actually).<br /><br />Things like somatic mutation and gene-environmental interactions would not, nor would the changing landscape of how we phenotype individuals, and so on. So the data would be of limited, and over time greatly diminishing value.<br /><br />Right now, to me, a major issue is the spending of public funds on diminishing returns, when we have many clear, even clearly genetic, traits we should be investing a full fusillade of resources to do something about, rather than toying around with countless trivially weak, ephemeral factors.<br /><br />But, of course, it's just my view!<br />And thanks for the final compliment. Trying to be thoughtful and thought-provoking is our objective!Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-37999616128609367362013-08-07T05:50:42.774-04:002013-08-07T05:50:42.774-04:00A couple of points in response. I won't focus ...A couple of points in response. I won't focus on prediction much, as its issues have been well covered in your posts and comments, and I don't feel qualified to opine on science policy/funding, as I don't know the current structure well enough.<br /><br />Private vs. public money. I answered why I would (and did) get myself genotyped. I wholeheartedly agree that genomic prediction does not currently give medically useful information for majority of the traits, and do not argue (here) that a lot more genotyping should be done with public money. But for my private hobby, it has been worth it for the fun, and finding some long lost second cousins in far countries.<br /><br />"GWASing everything that moves". I think that if the genotype data have been collected with appropriate consent, it would be silly _not_ to map all the measured traits. GWAS do have the potential of uncovering actionable alleles, and furthering our understanding of the underlying biology.<br /><br />Privacy issues. I agree these are real. I only understood the real implications of 23andMe terms and conditions after receiving the data. In short, they are free to sell my anonymised data on to drug companies. And given recent internet surveillance revelations, I have no doubt the US government could also obtain them. I am not happy about either.<br /><br />I don't think somatic mosaicism and tissue-specific expression would be a major factor in decisions to genotype, and do believe genetic counselors would be able to give better advice if they had all the information (all the sequence data) available.<br /><br />All in all - time will tell, as has been a conclusion above and below. By the way, while it's my first time commenting, I've been enjoying your thorough, thoughtful posts for a while now; thank you for the content!Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-65445954935575033542013-08-06T11:29:35.048-04:002013-08-06T11:29:35.048-04:00I basically agree, but we have an honest disagreem...I basically agree, but we have an honest disagreement about the relative worth of different directions science should take. <br /><br />If the clear-cut diseases haven't yielded, then either we should focus on doing something to change that, or decide that we need some very different approach. Chasing down the multitude of individually unique minor contributing factors doesn't seem to me to be right, and I personally think mainly reflects inertia, and vested interests, that mitigate against more measured consideration of what should and can be done.<br /><br />So, I guess I just come down more on the pessimistic side of the Big Data issues. On the other hand, I think technology is very powerful, so I'm more optimistic about the eventual ability to engineer some solutions to the things that really are meaningfully genetic.Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-9052012574631698842013-08-06T11:23:33.339-04:002013-08-06T11:23:33.339-04:00I'm in complete agreement that, as a society, ...I'm in complete agreement that, as a society, we could reap more and faster benefit from behavior change. Just look at tobacco. But large-scale changes in the population don't come easy, and disease prevalence can't be eliminated, just reduced, so we need better medicine regardless.<br /><br />It's good to question how we spend our funds, and I'm sure it's easy to find misapplied funding in the biomedical field. Nonetheless, the life-spoiling diseases with a clear genetic basis, even single-gene diseases, have largely proven non-amenable to clear, focused research using our prior methods and technologies. We need more power to better understand the biology, and genomics gives us a valid starting point IMO, although it's the downstream research--RNA and proteins--that may well give us more of the medical solutions we seek.<br /><br />I'll admit, my perspective is influenced by a persistent optimism that we can make hay from the massive data haystacks we obtain from omics research. That said, I don't think we'll understand it all, just enough to substantively improve the delivery of medicine to individual patients over time. YMMV, but to me that's worth the investment.Mark Wannerhttp://community.jax.org/genetics_health/b/weblog/default.aspxnoreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-26375025805933994202013-08-06T10:04:09.987-04:002013-08-06T10:04:09.987-04:00Thanks, Mark! Genomic medicine is a huge field, a...Thanks, Mark! Genomic medicine is a huge field, and I totally accept that there are aspects that are very useful (genotyping tumors is a big one, e.g., genotyping to determine useful therapies for a number of diseases, etc.). People often say what you do, essentially that massive amounts of sequence data will lead us to understand what it all means. But it seems that, to date, the more we know the *more* complex everything is rather than less. I suspect we already know the answer -- life is complex.Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-38856555555384761512013-08-06T10:01:13.104-04:002013-08-06T10:01:13.104-04:00To me the question is rather a political or ethic...To me the question is rather a political or ethical one. Is this going to lead to abuse of our notions of confidentiality and equity, or to discrimination and profiteering at our expense. <br /><br />And, is there a better way to spend limited public (or even private) funds? Personally, I believe that we know of many problems that are clear, focused, and should be amenable to proper science. There are all sorts of life-spoiling diseases with a clear genetic basis, for example. People do work on them, but rather than all the flailing about by the omics world, I think we should stop that little-sense and focus intensely on the known, hopefully tractable problems.<br /><br />This also would serve as proof of principle for extending the same kinds of effort to less clear problems. We have a few successes, but nowhere near what we should if current investment policies were about general well-being rather than well-being for professors, university administrations, and genome tech companies.<br /><br />Plus, we already know very well that non-technical adjustments for most of the diseases in question would have far, far greater impact on actual people's health than the technical stuff we're up to.<br /><br />Engineering society is probably harder to do than engineering genes, which we're already hard-pressed to do very well. But at least lifestyle changes should cost less and do more. If only we had enough cogent research to know how....Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-19112203036706996862013-08-06T09:54:44.808-04:002013-08-06T09:54:44.808-04:00Holly's comment made me laugh. I give tours/ta...Holly's comment made me laugh. I give tours/talks about genomics and genomic medicine, which personally I find very compelling. Nonetheless I say that I would support anyone's decision to get genetic information from a DTC company only if they take the view that it's likely going to yield entertainment for the most part, not useful understanding. The predictive power is about as good as you'll get from a phone-in psychic at this point.<br /><br />I am about to get WGS for myself for a couple of reasons though. First is simple curiosity, as mentioned by the first commenter. Second is to add my data to the pool (I'm in PGP) in hopes that if we can sequence millions and one day figure out how to share and manage the data, not to mention all the ELSI stuff, we'll find out some really useful things along the way. Still probabilistic and not predictive most likely, but useful nonetheless.Mark Wannerhttp://community.jax.org/genetics_health/b/weblog/default.aspxnoreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-45145369150226888862013-08-06T09:35:51.940-04:002013-08-06T09:35:51.940-04:00If anybody really wants truth, it's worse than...If anybody really wants truth, it's worse than what you say, Anne. That's because if your actual risk (largely unknown if not unknowable) for disease X is changed--either because the estimate changes or because the biological facts change due to circumstances, like diet or taking statins, then your risk of something else actually RISES! You have to get something, after all!<br /><br />But there is little way at present to know what that something will be. And, if it is delayed you may have longer to life, but will those added months or years be worth it, or will it just mean more debilitated end-of-life?<br /><br />Nobody wants to talk about these hard realities.Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-9505511276452006112013-08-06T09:32:48.673-04:002013-08-06T09:32:48.673-04:00Indeed. Even more perplexing, your risk might be ...Indeed. Even more perplexing, your risk might be 37% today, but 27% or 47% next week, because new studies have reported new estimates. <br /><br />But, risk is elusive and ephemeral for other reasons. As Muin Khoury points out <a href="http://blogs.cdc.gov/genomics/2012/07/26/think-after-you-spit/" rel="nofollow">here</a>, "below average" and "above average" risk are only relative concepts. <br /><br />"The meaning of “above average” and “below average” life time risks of disease is still based on incomplete scientific data and needs to be interpreted in the context of how common the disease is and the person’s other risk factors. In other words, a “below average” risk of heart disease will still mean a high risk of heart disease since heart disease is very common, whereas an “above average” risk of multiple sclerosis will still mean a low risk since the disease is much less common than heart disease." Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-29506853192356002682013-08-06T09:32:00.838-04:002013-08-06T09:32:00.838-04:00There are (at least) two important issues. First,...There are (at least) two important issues. First, is the risk estimate accurate and is there a way to know?<br /><br />Second, how does my individual risk relate to the group risk which is what predictions are essentially about, despite what they say (we have an earlier series of posts about the nature of such statistical estimates and their assumptions about causality).<br /><br />In some cases, public health risks (group risks) are very useful. Fluoridated water or iodized salt, perhaps vitamin D in milk are examples. Everyone, or at least most by far, benefit in similar ways. Risk of disease in the absence of these measures can at least be estimated with some reliability.<br /><br />But we have little way to know how these kinds of risk, based on collections of specific measured factors (alleles across the genome) estimated from cases and controls or similar data, apply to individuals.<br /><br />One way to think about it is to ask what is the variance around the mean risk estimate? Is it narrow, in which case you're close to the group mean risk, or is it wide, in which case the risk estimate is rather meaningless. For many reasons, even this is only a heuristic way to think, because the methods of obtaining data and estimating risk introduce this 'variance' in ways that have to do with the analysis as much as with the underlying causal reality (we tried to deal with these issues in those earlier posts)Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-6599068159542316352013-08-06T09:23:26.226-04:002013-08-06T09:23:26.226-04:00And how does anyone know whether their risk estima...And how does anyone know whether their risk estimate of 37% for heart disease is accurate? And that, therefore, they spent their money wisely? This is why paying for 23andMe to get their "health reports" is compared to paying for a fortune from a fortune-teller with a crystal ball. Holly Dunsworthhttps://www.blogger.com/profile/05260104967932801186noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-56942147515556295912013-08-06T08:48:35.431-04:002013-08-06T08:48:35.431-04:00Thank you. Clearly, these are compelling reasons f...Thank you. Clearly, these are compelling reasons for many people. Of all your reasons, to me, curiosity is the most appealing. But the answers to any questions I'd wonder about, including ancestry, would be so ephemeral that, to me, it's not a good enough reason.<br /><br />An important thing we forgot to mention in the post is that not only are future environments unpredictable, the fact that everyone's genome is unique makes predicting the effect of a given mutation difficult, given that genomic background has an effect. And then if you factor in the unpredictability of future environmental exposures, it becomes let's call it a crap shoot to predict disease (some variants are more predictive, it's true, but these tend to be for rare diseases). And that's true even when everyone doing the predicting is using the same protocol, which is currently not the case.Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-26708128724138142902013-08-06T08:00:31.349-04:002013-08-06T08:00:31.349-04:00These are some good reasons for genomic data colle...These are some good reasons for genomic data collection and use. Personally, I think one cannot trust, at all, what private interests like '23' will do with the data. <br /><br />If there were not some real epistemic issues that are being largely swept under the rug, and if/when whole genome sequencing etc becomes truly affordable on a large scale, then developing whole-population registries would have a lot of appeal.<br /><br />But the data (made confidential, to the extent possible) should be made public, and collected by personally disinterested government staff. That is, not a huge boondoggle for some university professors, and public immediately, not after a moratorium that let some investigators mine it for publications.<br /><br />The real sticking points are the idea that DNA sequence is all you inherit that's relevant, that the 'constitutive' genotype (from saliva, cheek swab, blood sample) is your only genotype (see some last-week posts on MT if you missed them), that tissue-specific gene expression is what counts, and that non-genetic (environmental, whatever that may include) variables are not adequately measured or, in many instances, measurable or predictable.<br /><br />Given these issues, I personally think that exhaustive data collection is not the optimum way to invest science resources, especially in regard to public health<br /><br />For your point #3, issues about Mendelian disease are also much more subtle than widely realized, but genetic counselors already can do that, and competently and not-for-profit (i.e., no ulterior motive).<br /><br />We don't really need the continued GWASing of everything that moves to address your point #2. <br /><br />Whether this is cumulative knowledge or basically vaporware is debatable, and I think it is far from obvious that the knowledge is very valuable or, after a few years, would even be looked at except by historians. Time will tell, on all of these fronts.<br /><br />But not to worry: for those, like you and many others, who like this trend in events, it is a reality that isn't going to be slowed. After all, '23' has begun a major advertising campaign, apparently playing on fear (of disease). So this business is booming, regardless of critics or skeptics.Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-68342852129542147212013-08-06T05:59:24.226-04:002013-08-06T05:59:24.226-04:00I only have 23andMe genotype data, not sequencing,...I only have 23andMe genotype data, not sequencing, but would also pay a small fee for the latter. I agree genomic prediction using common alleles is not well powered at the moment (and in many cases, in principle) to give answers that would motivate me to take any action. It's mostly for curiosity, some current utility, and some investment to potential future utility that I got myself typed.<br /><br />1) Curiosity about ancestry. With reference panels from all around the world, individual haplotypes can be traced to founder populations for an illuminating picture of "where I come from", while birth records only go back a century or two.<br />2) Actionable large effect alleles (drug dosing, BRCA). Recently, a family member had trouble during surgery due to increased warfarin sensitivity that could have been prevented (or at least the surgeons notified) with this information at hand. <br />3) Carrier status for severe Mendelian diseases. When planning kids, we could double check whether conditions and alleles not covered by common tests (or tests not available in our country) have potential to yield compound heterozygosity that we should test for.<br />4) Cumulative gain of knowledge over time. There has only been about a decade of sequencing and array powered genomic discovery, I am sure the utility of genotyping data will increase with time.<br />5) Contributing my genome data to understanding. Some heritable traits are quaintly interesting (e.g. detached earlobes), but should not be spent public money on for mapping. For some large reference panels (like 23andMe is amassing), gathering information on such traits is cheap, and my data can help in the mapping. Anonymousnoreply@blogger.com