23andMe, deCODEme and Navigenics at Cold Spring Harbor

Just in case anyone has been wondering why I've been so quiet, I'm in beautiful Cold Spring Harbor this week for the Biology of Genomes meeting. Be warned that I'll have a lot more to say about this meeting once I've recovered from the combined effects of jet-lag and the punishing schedule (last night's evening session finished at 11:30pm!), most of which will include the words "next", "generation", "sequencing" and "wow".

For now, I want to download some thoughts on this afternoon's panel discussion on direct-to-consumer genetic testing between three giants of the personal genomics industry: 23andMe's Linda Avey, deCODEme's Kari Stephansson and Navigenics' Dietrich Stephan. The session was ably chaired by the former head of the public Human Genome Project, Francis Collins.

Each of the three company representatives was given around 10 minutes to push their vision for the personal genomics industry. While all three are selling essentially the same product (a read-out of between 500,000 and 1,000,000 variable positions from your genome), each did their best to differentiate their company from the competition.

Navigenics was first off the mark, and the tone was serious: Western society is headed for a healthcare crisis, with the combination of an ageing population with an increasing frequency of lifestyle diseases like obesity and diabetes leading us inexorably towards an increased load of common diseases. Within a generation, said Stephan, we need a solution, and the only solution is early prediction and intervention.

The Navigenics message has remained on target since its launch a month ago: this is a careful, serious, completely disease-focused company. Stephan talked up the quality control on the Navigenics testing service, which includes repeating any disease-related genotype calls that fail the first time around (unlike 23andMe and deCODEme). He also emphatically stated what Navigenics wasn't: the company will never offer testing of genetic predictors of non-disease traits like height or eye colour; will never offer genetic ancestry testing; and will not offer comparisons of family members (apparently out of concerns about unexpected discoveries of non-paternity). This is, of course, an explicit attempt to portray the competitors - who both offer both ancestry, trait prediction - as frivolous.

Next off the rank was Google-funded 23andMe. Avey immediately turned Stephan's accusation back on itself: rather than being frivolous, 23andMe simply "looks at genetics holistically", with information on non-disease traits and ancestry being part of the big picture that customers want ("genealogy is the second most popular hobby on the internet," she said. "You can guess what the most popular one is.")

Avey explained that her decision to found 23andMe was based on her frustrating experiences at Perlegen attempting to recruit large cohorts of patients to use for large-scale genetics, and during her talk there was a strong emphasis on 23andMe as a system for driving genetic research. Just as the internet-based communities of Web 2.0 are willing to share their information with one another and reap the benefits, 23andMe is apparently aiming to create "Research 2.0", in which patients volunteer their genetic and clinical information for researchers to work with, and then use the results of that research to inform their own lifestyle decisions. Avey cutely terms this model "23andWe".

Finally, the intimidating Viking-like figure of Kari Stephansson took to the platform. Stephansson played continuously on the research cred of deCODEme's parent company, deCODE - not without justification, given the impressive list of large-scale genetic studies performed by the company (which Stephansson rather heavy-handedly flashed up on the screen, one by one, for what seemed like forever).

In fact, these distinguished scientific credentials seemed to be pretty much the only thing Stephansson could find to distinguish deCODEme from its rivals. Otherwise, the deCODEme ethos seems to resemble the open information model of 23andMe rather than the more old-fashioned paternalistic approach of Navigenics. "Is it always laudable when people learn more about themselves?" he asked, and argued that the answer was unambiguously yes. "Our customers will benefit from knowing themselves better."

After the three company talks, there were presentations from Johns Hopkins' Kathy Hudson and the National Coalition for Health Professional Education in Genetics' Joseph McInerney. Hudson emphasised the strong appetite of consumers for genetic information, and the desperate need for empirical data regarding the responses of people to information about genetic risk variants (which I've wondered about myself). McInerney made a strong case for the complete under-preparedness of health care providers for the boom in personal genetics, and introduced a new database called GeneFacts (currently under development) which will store expert-curated information about genetic tests for both consumers and health providers.

The following discussion was lively, and nowhere near as hostile as I expected. A few highlights:

• Stephansson was remarkably candid about the usefulness of current tests involving common variants (which all three companies rely on): in one exchange he noted that "we are marketing these tests without any claim that they will impact on people's lives"; in another, he admitted that common variants probably provide marginal utility beyond simply collecting general information on family history.

• Kathy Hudson responded to the problem of patients being given data of very limited predictive value with a very sensible solution: "In the absence of demonstrable harm, the default should be to provide the information." In her talk, she referred to the argument that genetic tests should only be ordered through a health-care provider as "an old-fashioned model" - a clear rebuff to both Navigenics, which boasts about using an in-house doctor to authorise all of its tests, and the American College of Medical Genetics, which recently issued a statement which argues that "a knowledgeable health professional should be involved in the process of ordering and interpreting a genetic test".

• Stephansson was sceptical of Avey's claims that 23andMe can perform useful research, given the limitations of self-reported data (I agree). Avey explained that this problem is one of the reasons why 23andMe is interested in working with companies like Google to integrate genetic data with medical records - a suggestion that resulted in some shocked muttering from the audience.

• Eric Lander (founding director of the Broad Institute) suggested that the medical genetics community needs to play a stronger role in the field of personal genetics, possibly contributing to some sort of expert-curated wiki-style database of information about genetic associations. He indicated that this couldn't be privately funded due to conflicts of interest. McInerney suggested that the soon-to-arrive GeneFacts database could serve as a starting point; Hudson stated that there has been substantial discussion about a genetic test registry at the Genetics & Public Policy Center, and that clear support from the medical genetics community would help this move forward. It appears that DNA Perspectives may have some competition in the very near future. Either way, this is good news for genetic test consumers.

• There was an interesting back-and-forth between Stephan and Stephansson over the issue of ancestry testing both in their talks and in the discussion: Stephan basically sees ancestry testing as a distraction from the serious business of disease, while Stephansson argued that the effect size of disease risk variants frequently varies between populations, so ancestry testing is highly relevant to calculations of disease risk. This is an empirical question that will soon be answerable (deCODE is apparently currently investing in association studies in Asian populations).

• All three of the company representatives mentioned their interest in developing whole-genome sequencing capabilities, which is unsurprising - sequencing has always been the Holy Grail of personal genomics, with the current SNP chip technology really little more than a crude place-holder until sequencing prices drop.

I also chatted with both Stephan and Avey after the session - for what it's worth, they're both extremely personable, and there was no overt animosity between any of the three competitors (somewhat to the disappointment of the audience, I suspect).

Anyway, that's the bulk of the personal genomics component of this meeting. As I hinted at the beginning of the post, the other main message has been the rapid advance in next-generation sequencing technology and its application to human genomes, which I'll hopefully be able to post about over the next few days.

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David Altshuler on personal genomics

The Boston Globe has a fairly well-balanced article on the current state of personal genomics: a field with tremendous promise that is yet to really deliver. I particularly liked these two contrasting quotes from David Altshuler of the Broad Institute:

"From a clinical point of view, [current genome scans are] just noise," he said. "No one knows how to use such information to improve health."

and

In coming years, Altshuler says, he believes genomics will be as transformative as the Internet.

The first quote is only slightly exaggerated; the second is spot-on.

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A new model for genetic privacy: you don't have any

In a perspective piece in Nature Reviews Genetics (subscription required, I think), Personal Genome Project leader George Church and colleagues advocate a revolutionary new approach to research subject privacy. Essentially, they argue that "the reality of the new genetics and genomics urges us to abandon the traditional concept of medical confidentiality". In other words, research participants must learn to accept the fact that the privacy of their genetic and health information cannot be guaranteed.

When I first heard of this concept in the context of the Personal Genome Project it struck me as pure insanity - who would volunteer for a project if there is a significant risk of your genetic and health information being accessed by (say) insurance companies? Having thought it over, though, the need for such an approach is becoming more and more clear to me. The basic argument goes something like this:

1. Your DNA sequence (or any sufficiently large set of genetic markers, like those used in modern genome-wide association studies) is enough by itself to unambiguously identify you.

2. Thus even "anonymous" participants in large-scale genetic studies are vulnerable to having their identity revealed - all it would take is someone to have a sample of your DNA, and access to the individual data-points from the study, and they would then have access to any health or life-style information recorded about you as part of that study.

3. As such, there simply cannot be guarantees of anonymity given to participants in such studies, fundamentally undermining the traditional model of confidentiality.

4. The best solution to this problem is to abandon the illusion of research subject privacy, and instead recruit participants with the explicit condition that all of the data collected about them as part of the study may in fact be revealed to the public.

The authors aren't advocating a complete dump of participant genetic and health records on a publically accessible website - although volunteers in the Personal Genome Project have the option of doing just that, should they choose to. Rather, they argue for a strategy of "maximizing data protection while informing people about its limits". In other words, doing your best to limit disclosure of individual health data, while clearly informing participants of the fact that their privacy can't be guaranteed.

It certainly is an audacious paradigm shift, and I'm having trouble predicting its consequences. For instance, will such a policy discourage people with a clear family history of genetic disease from participating in large-scale cohort studies (for insurance reasons), thus reducing the power of such studies to detect disease-associated variants? Will it create a generation gap in research participation, with conservative older people shunning studies while the children of the Facebook era - who engage in public disclosure of information with a wilfulness that seems shocking to their elders - embrace participation? I don't know, but I guess we'll all find out sooner rather than later...

Anyone interested in the Personal Genome Project (which is calling for volunteers for whole-genome sequencing, by the way) should check out their informative web-site. Misha Angrist, one of the "First Ten" participants who will have their genomes sequenced by the PGP, also has a blog that's well worth adding to your RSS reader.

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Navigenics vs 23andMe: drawing the battle-lines

Well, the debut of Navigenics has certainly been a lot more interesting than I anticipated. Far from being just another genome-scan product limping along in the wake of 23andMe (like, say, SeqWright's rather depressing effort), Navigenics is brazenly attempting to re-define the entire industry in a way that suits them.

At the very least, the company is staking a solid claim over the lucrative well-paid over-30 non-geek market niche, which has been surprisingly poorly tapped by the current players. But Navigenics seems to want to go further than this: in fact, they appear to be trying to reshape the personal genomics industry as being first and foremost about the sober provision of evidence-based health information, and simultaneously position themselves as the most respectable provider of this information. If in the process they can create a perception of their competitors (particularly 23andMe) as frivolous and over-hyped, so much the better.

Over at Genetics and Health, Elaine Warburton has a long interview with Navigenics' Medical Director Michael Nierenberg. This is by no means a probing critique - in fact, it reads suspiciously like an extended advertisement for the company - but there are some interesting snippets from Nierenberg about the image Navigenics wishes to present:

Navigenics is no way a ‘recreational’ genomics company and does not wish to contemplate entering any ‘recreational’ field. It is a company focusing on the wellness and prevention aspects of health. Our service focuses on actionable entities and things of substance such as cardiac disease, not eye colour or such like. We welcome regulation and make heavy use of genetic counseling.

The sub-text is abundantly clear: we'll give you accurate information about the really important stuff like cancer and heart disease, whereas our competitors (they know who they are!) mess about with trivial information about athletic performance and ear-wax consistency.

Navigenics' well-orchestrated marketing campaign revolves around this central theme of seriousness and competence, and I'm sure the message is sinking in with their apparent target audience (well-paid, highly-educated, time-poor executive types old enough to start fretting about their long-term health); having the reliably earnest Al Gore spruik the company certainly didn't hurt. To emphasise their trustworthy seriousness, Navigenics has launched a joint study with the Mayo Clinic into the effects on patients of receiving genetic information, is partnering with Medscape to provide physician education, and proposed a set of standards for personal genomics companies (a clear attempt to re-define the industry in their own image, while simultaneously seizing the moral high ground).

Through these activities, as well as their use of CLIA-certified genotyping facilities and provision of 24-hour access to genetic counselling, the company no doubt hopes to avoid many of the criticisms thrown at other personal genomics companies.

This all seems quite admirable, on the whole. However, the Navigenics model is also deeply regressive: they are taking the currently exciting, somewhat anarchic but intrinsically empowering field of personal genomics (in which individuals are free to explore their own genetic data however they wish) and cramming it back into the tightly-regulated, paternalistic environment of the standard medical framework. Where 23andMe talks about guiding customers through their own journey of genetic discovery, Navigenics appears to be more about giving clients the information that Navigenics thinks is medically relevant, and protecting them from all the non-essential details that might overwhelm or confuse them.

Nowhere is this regressive paradigm more evident than in Navigenics' refusal reluctance to give their customers access to more than a tiny fraction of their own genotyping results. Unlike 23andMe and deCODEme, who both freely provide clients with access to their complete, raw genotyping data, Navigenics customers must sign a waiver to receive their results on an encrypted disk (presumably without an easy-to-navigate interface); Navigenics ominously warns that "without our blessing, the potential for misinformation is extremely high" (updated thanks to Hsien). Elaine puts a positive spin on this reluctance:

Imagine the confusion and furore if Navigenics were to provide its members with their full 1 million marker analysis! Navigenics’ (and others) sensible, if somewhat patriarchal approach of ‘drip feeding’ results to members as and when the research is robust enough to bring the SNP into the public domain, is one that should be applauded not derided.

In other words, customers shouldn't need to worry their pretty little heads over all these confusing As, Cs, Gs and Ts - they can just let Navigenics decide what they need to know. Ouch.

I can only assume that Navigenics' focus group research suggests that their target audience finds this attitude reassuring rather than profoundly insulting; either way, it's both patronising and unnecessary. After all, it's not like 23andMe simply punt any old genetic association out there for their customers to sift through - they carefully code the associations to indicate how reliable they are (based on a pretty reasonable set of criteria [PDF], I might add). Customers are allowed to analyse their own data for both gold-standard and lower-reliability associations, but are given information to help them decide how much weight they should place on each. In my opinion this sort of informed freedom is a far more enlightening (and vastly less insulting) model that the constrained "need-to-know" approach of Navigenics.

Anyway, it will be interesting to see how Navigenics alters the long-term tone of the personal genomics market. Perhaps the early pioneering feel of personal genomics was just a temporary aberration, and we are now seeing the beginning of a general regressive shift towards the standard medical model. More optimistically, I suspect these early battle-lines mark the beginning of a diversification of the industry, with some products targeting the individualistic and curious spirit of a younger, information-savvy generation, and others appealing to the more serious health-centered focus of individuals moving towards middle age.

Either way, it will be fascinating to watch 23andMe, Navigenics and their current and upcoming competitors struggling to define an entire industry as they battle for market share.

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Ready or not, personal genomics is here

A new editorial in Nature comments on the rapidly expanding field of personal genomics. The appearance of this industry has taken many observers by surprise; indeed, the authors note, "Rarely have basic discoveries morphed into a commercial product quite so swiftly."

The speed of the industry's growth has led to many calls for heavy regulation, which (I think) would be a disastrous approach for consumers. Nature agrees, and offers a positive alternative solution:

If consumers are to reap the benefits that genetic testing can offer, they need understandable information about the basis, validity and limitations of the tests. One proposed structure for providing this information is a publicly accessible registry into which test-makers would be required to upload data about their tests and the studies that back them. This information should be updated as genetic risks are changed or refined, as inevitably they will be.

There are already some similar databases that currently exist (such as the Wikipedia-like SNPedia) or are being planned (e.g. GEN2PHEN [PDF]), although none of them are yet comprehensive or rigorous enough to fulfil the needs of genetic test consumers. It would be great to see these and similar efforts promoted and funded, or perhaps even combined in a central registry that supplements slow, careful expert annotation with the faster but looser community-driven SNPedia approach. It would almost certainly be more cost-effective to build on existing projects rather than developing a new registry from scratch.

However the registry develops, Nature's point is that the solution to shonky genetic test vendors isn't just legislation (which, if too heavy-handed, will also negatively affect legitimate companies and limit consumer choice), it's also information. Providing potential customers with reliable data about the efficacy of genetic tests and allowing them to make their own decisions protects consumers without sacrificing their autonomy. This is certainly my philosophy, and the motivation behind Genetic Future - it's very reassuring to see that this sentiment is shared in the lofty reaches of the Nature editorial board.

The article finishes with pertinent advice to consumers:

In the meantime, online shoppers who buy genetic tests would do well to keep asking themselves whether the science is, indeed, ready.

Before buying any genetic test, research widely about its pros and cons, and think hard about whether the information you receive will really be worth the money you spend, or whether you'd be better to save your money until better tests are available.

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Personal genomics: getting your money's worth

Over at Eye on DNA, Hsien-Hsien Lei has an entertaining list of the variety of personal genomics services that could be purchased for the $2,500 cost of a full Navigenics scan. There's some tough decisions in there: would I prefer two paternity tests, or sixteen genetic tests predicting my risk for baldness?

Hsien points out that at the current going rates of the sole company offering commercial whole-genome sequencing, $2,500 would buy you only 0.71% of a whole genome. That sounds small, but it's still more than 20 million base pairs - twenty times the paltry one million sites interrogated by the Navigenics chip for the same price!

Of course, the Navigenics SNPs have been carefully selected to provide as much information as possible about common genetic variation, so they're still a better purchase right now than a random 0.71% of a genome sequence. Nonetheless, this comparison provides some insight into just how cheap sequencing technology is becoming; it certainly won't be long before it's commercially competitive.

As I've emphasised in recent posts, the chip technology currently used to analyse genetic variation by researchers and personal genomics companies (23andMe, deCODEme, SeqWright and now Navigenics) will only ever capture a fraction of your total genetic risk for common disease: the fraction that consists of common small-scale variants.

In contrast, whole-genome sequencing will give you information about the types of genetic variation - such as rare variants and large-scale structural variation - that are completely invisible to current chips. Since these variants probably constitute a substantial fraction of genetic risk for common diseases, sequencing (when it becomes affordable) is likely to give you a lot more useful information than current genome scans. And best of all, since whole-genome sequencing gives you information on every variation in your genome, it won't ever become obsolete - whereas chips will be periodically replaced by new, higher-resolution models that capture a larger (but still incomplete) snapshot of your genetic variation.

In other words, while genome scans are the best affordable technology we have right now, they have profound limitations and will become rapidly outdated as researchers begin to focus on the rare variants and structural variation that contribute to variation in complex traits and common disease risk. For those who care about value for money, my suggestion is that you put your $2,500 in a bank account with a good interest rate and don't take it out until whole-genome sequencing becomes cheap enough to buy that instead.

Of course, that's advice for those who are mainly interested in health prediction. For genetic genealogists current genome scans provide some powerful information about genetic ancestry; if that's your interest, you'd probably be best off investing in a deCODEme scan, which gives you the same number of SNPs as Navigenics for 40% of the price, and (unlike Navigenics) allows you to download your complete raw data.


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Some early thoughts on Navigenics

It's been a long, long wait, but Navigenics has finally officially entered the personal genomics arena. Like the Me Two (23andMe and deCODEme), Navigenics will be offering to determine the sequence at hundreds of thousands of commonly variable positions throughout your genome, which it will use to make predictions about your risk for a variety of common diseases such as heart disease and type 2 diabetes. The service will cost US$2,500, compared to US$1,000 for the two major competing offers.

The Wired blog has the facts. A few early thoughts:

1. Navigenics would probably struggle to compete head-to-head with 23andMe, which has a much stronger public profile, a funkier website, and offers a significantly cheaper service (albeit with fewer markers); BUT
   

2. It's pretty clear they're aiming at a different market niche altogether. Just compare the two websites (23andMe, Navigenics): 23andMe will appeal more to the hip young web-savvy childless yuppie who wants to know more about him/herself and build up some cool conversation topics (their website is all about "Your personal journey of genetic discovery"); Navigenics is aiming for the sober, older executive with kids who watches their weight and cholesterol and heads to the gym three times a week (website quote: "I want to be part of all the big moments in my son's life, so I'm doing everything I can to stay healthy.")

3. Providing access to genetic counselling and promoting physician education, while certainly praise-worthy, is all part of this market positioning. Navigenics is trying to say that they're above all the hype and frivolity of 23andMe; all they care about is your future health, and they care about that in a deeply earnest, professional yet compassionate manner. (The genetic counselling video sums up the mood nicely.)

4. Navigenics has started with a genotyping service that is CLIA-certified - unlike 23andMe, who had to change labs to a CLIA-certified facility a few weeks back (causing disruptions to their service).

5. Navigenics offers a long-term DNA storage service, which is a clever business move. It will be that much easier to convince customers to purchase an extra DNA test in a year's time - or whole-genome sequencing in five years' time - if they don't have to go through the hassle of re-submitting a mouth swab. Never underestimate the role of convenience in shaping consumer decisions.

6. The "relative lifetime risk" analysis offered by Navigenics seems as though it will provide more impressive-sounding numbers than the absolute risk estimates offered by 23andMe and deCODEme, but I'm not sure how statistically sound it is to extrapolate odds ratios from genetic association studies to total lifetime risk (especially given that the strength of genetic associations is known to vary with age). Would any statisticians out there care to dissect Navigenics' white paper on their methods?

7. Finally - and this is completely a personal thing - there's absolutely no way I'd buy into a service that didn't provide me with complete and unfettered access to my raw SNP data. Both 23andMe and deCODEme offer customers the ability to download and analyse their own data; this isn't the case for Navigenics, according to the Wired article. That's a complete deal-breaker for me, but admittedly it's unlikely to have much of an impact on the chiselled, athletic executive types featured on Navigenics' front page, who (understandably) have no particular interest in the raw data but simply want to know their risk of stroke and heart disease (presumably so they can stay alive and healthy long enough to play football with their chiselled, athletic kids).

Cynicism aside, I've got to hand it to Navigenics: they've managed to neatly differentiate themselves from the competition, and they're now poised to capture a lucrative high-income section of the market that has been surprisingly poorly targeted by existing personal genomics companies.

Anyway, you'll no doubt read a lot more about this over the next day or two. Genetics and Health has an ongoing (and thus far relentlessly positive) series of posts on Navigenics. I'm particularly interested to see what Steve Murphy has to say - it seems to me that Navigenics has managed to avoid most of the problems that he's been slamming 23andMe for over the last few months.

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More on the 23andMe lab change-over

I pointed yesterday to 23andMe's apology and explanation for significant delays in sending out genotyping results to customers - apparently a change of lab was to blame, driven by the need to shift their facility to a CLIA-certified venue.

Our Gene Sherpa Steve Murphy has a lot more to say about this, include a challenge to 23andMe to repeat the assays for all clients that have already been genotyped and compare the two data-sets. I personally don't think that's necessary, although it would be a powerful symbol of openness for the company to release some more detailed results of the comparisons between results between the old and new facilities (at least to its customers, if not to the rest of us riff-raff).

Disclaimers or no disclaimers, people are taking the results of these tests seriously. Failing to act quickly and strongly to reassure the community that their personal genomic data are sound would further undermine an industry that is already being subjected to considerable media scepticism.

That said, if I were in the first batch of customers I'd still be feeling pretty confident about my data. Steve suggests that the stated <0.1% discrepancy between the old and new labs represents "a whole ton of SNPs"; I'd respond that it means that for any given SNP of interest, there's at most a 1 in 1000 chance that your data are incorrect. That strikes me as a thoroughly acceptable error rate given how small an emphasis I'm likely to place on any one SNP when considering making changes to my lifestyle.

Update: In the comments, Ann Turner points to her recent comparison of 23andMe and deCODEme data from the same individual on RootsWeb. For the 560,128 SNPs for which both companies called a genotype, only 35 were different between the two platforms - that's an astoundingly low discrepancy rate of just 6.25 differences per one hundred thousand SNPs! Slightly more worrying is 23andMe's missing data rate of 3.5 per 1000 SNPs (for SNPs that were called successfully by deCODEme), which is uncomfortably high to my liking, and compares unfavourably to deCODEme's missing rate of less than 1 per 1000 SNPs.


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23andMe delays explained

A couple of weeks ago I pointed to an anonymous LiveJournal entry in which "fdmts" complained about the delays in receiving his genome scan results from 23andMe. The LiveJournal entry quoted an email from the company explaining that they were "experiencing a backlog that is resulting in longer than predicted processing times".

23andMe founders Anne Wojcicki and Linda Avey (in their traditional, somewhat eye-hurting fluorescent pink attire) have now used the 23andMe blog The Spittoon to apologise and explain. It seems that the company has changed the lab used to perform their genotyping, and the transfer has resulted in an inevitable lag time.

Bearing in mind that 23andMe are at the forefront of a brand new industry involving complex technical and legal issues, such delays are not unexpected. It appears in this case that the change of lab was driven by regulatory requirements; the new lab is certified under the Clinical Laboratories Improvement Act of 1988 (CLIA).

I don't know enough about the regulatory environment in the U.S. to guess at whether this move is simply in order to stay ahead of the shifting demands of regulatory agencies, or whether it heralds a move towards a more clinical focus (something the company has explicitly steered away from so far). Any thoughts?


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Will information on risk genes actually change behaviour?

A recent news focus in Science is well worth a read if you're lucky enough to have an institutional subscription. If you don't have a subscription, my post a couple of days ago on the problems with genome-wide association studies covers some of its major points: the article describes the disappointing results from even extremely well-powered genome-wide association studies (in type 2 diabetes, for instance) and lists copy number variation, rare variants, population differences and epistasis as potential explanations.

The article also tackles the fascinating question of whether information on the types of small-effect risk genes identified by recent genome-wide studies is likely to have much of an effect on patient behaviour and disease outcomes.

Two years ago, behavioral epidemiologist Colleen McBride and human geneticist Lawrence Brody [...] offered volunteers in Detroit, Michigan, the chance to learn whether they carried deleterious variants for eight health conditions, including diabetes, colon cancer, and osteoporosis. Because the variants are common, virtually everyone was expected to harbor at least a couple. Those monitoring the study's safety "were really worried, literally, that people were going to jump off bridges" when they learned that their risk of disease was increased, says McBride.

Among the 300 or so who have participated, that hasn't happened--quite the opposite. "They're not having big emotional responses," says McBride. The researchers are tracking the volunteers to see whether the information affects decisions to reduce disease risk, such as seeking out a smoking-cessation program or consulting with a nutritionist.

Behavioral specialists have shifted from worrying about the devastating effects of learning about these new genetic risks to wondering whether the information will make any impression at all.

Patient indifference to genetic risk factors wouldn't come as a huge surprise to any clinician who has ever tried to convince a high-risk patient to cut down on dangerous activities for the sake of their health: smokers keep smoking even though the increased risk of heart and respiratory diseases is well-publicised.

However, it remains an open possibility that obtaining a personalised genetic risk profile will serve as a more effective spur to behaviour changes than generic "smoking is bad" messages from clinicians and public health organisations. The article mentions a study currently in progress to test this possibility in a cohort of smokers with a family history of Crohn's disease (smoking doubles the risk of this disease).

It's amazing that these sorts of studies haven't been done yet, given how important they are: if it turns out that genetic information doesn't reduce risk behaviour in the real world, then the impact on public health of the hundreds of millions of dollars spent on complex disease genetics may actually be very small. I'm hopeful that this won't be the case - but it would be nice to have some actual evidence one way or the other...

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Eye on DNA interviews Knome CEO

Hsien-Hsien Lei from Eye on DNA has an exclusive interview with Jorge Conde, CEO of Knome - the company that offers whole-genome sequencing to customers for a cool $350,000.

As I've said before, the first Knome customers will be getting a pretty rough deal: a vast sum of money forked out for a pretty minimal return in terms of useful information, given our currently dismal understanding of most of the genome. Conde does his best to make this prospect sound more attractive:

...these early adopters will also be pioneers in the personal genome revolution and will be amongst the first people in history to be fully sequenced. These participants will be on the cutting edge of science and medicine. They will have access to the latest information as it becomes available and those that are willing to learn as we learn (and can appreciate risk prediction and the changing nature of our scientific understanding) will be best positioned to benefit.

Certainly, the early adopters will experience the warm glow of the pioneer. And it's true that they'll have their genome sequence in hand to take advantage of each new research finding that pops up over the next five years. But by the time we have enough genetic information to make a genome sequence seriously useful - in, say, five to ten years - the cost of sequencing will be down by three orders of magnitude. That's when I'll be buying my sequence!

Of course, Dan Stoicescu and other Knome early adopters didn't decide to purchase their sequences through a cold, logical cost-benefit analysis. Stoicescu explained in a recent NY Times article that he views his purchase as "a kind of sponsorship" - in other words, his over-spending will pave the way for affordable genome sequencing for the rest of us.

In any case, as sequencing costs plummet the real money is going to lie in sequence interpretation - translating six billion DNA letters into useful medical information, and then conveying that complex information to a customer in terms they can understand. Conde's interview suggests that Knome has invested heavily in this process, which should put them in a good position to compete with the inevitable flotilla of genome sequencing companies that pop up over the next five years.

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Another editorial on personal genomics

I only have time to quote one paragraph from this recent editorial on "recreational genomics" in the European Journal of Human Genetics; the full text is freely available, so check it out.

It looks like we are getting more and more confident about some genetic associations, and can estimate individual risks of complex diseases more precisely that a year ago. Although the average inhabitant of Netherlands now has a lifetime risk of developing type II diabetes of 13%, for some people this might be 10 or 17% after testing. Whether this makes any difference to people is not known. Effective interventions to reduce a risk of 17% to the population average of 13% are not yet available. Whether paying US$300 or even $1000 helps to motivate people to follow-up their individual lifestyle advice is not known either.

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23andMe laboratory delays

In an anonymous LiveJournal entry, "fdmts" quotes an email allegedly received from 23andMe:

Dear FDMTS,

We wanted to acknowledge that you've been waiting longer than anticipated to receive your data from 23andMe. Our sincerest apologies for the delay; the laboratory analysis process typically takes 4-6 weeks, but we are experiencing a backlog that is resulting in longer than predicted processing times - up to about 10 weeks. We have taken several steps to expand our laboratory capacity and the efforts are yielding results now. You will be notified via email in the next few weeks as soon as your data are ready.

We've recently added new content to our Personal Genome Service that we hope you'll enjoy. Thanks so much for your patience and for choosing to join the growing 23andMe community.

Sincerely,
The 23andMe Team

If this is a real email (and again, I emphasise that this is an anonymous and unsourced web comment, so it may well not be), this could mean one of two things:

1. 23andMe has experienced much higher-than-expected demand for its personal genomics service; or
2. 23andMe is having problems with their genotyping technology.
   

It's impossible to know which without further information, but both are intrinsically very interesting (at least to me!). Anyone else out there experiencing delays in getting their 23andMe results back? Anyone from 23andMe care to comment?

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deCODE's lay-offs: market saturation, or just one struggling company?

Eye on DNA's Hsien-Hsien Lei notes the recent lay-off of around 60 employees from deCODE genetics, the company responsible for personal genomics venture deCODEme. In a press-release quoted by Hsien, deCODE CEO Kari Stefansson suggests that this is a broader omen of things to come within the personal genetics community:

It is natural for us to operate the company in such a way that we can make the money that we have last longer than what we had expected to begin with. These are very simple and clear operational standpoints and it would even be wise for other companies in our community to follow our example.

Hsien goes on to suggest that deCODE's troubles may stem from a premature expansion of the personal genetics market in the absence of real consumer demand:

Perhaps this is an indication that the market is starting to experience saturation in the number of companies and services being offered yet has not seen a concomitant rise in the number of consumers willing to pay for personal genomic services.

I'm sceptical that the personal genetics market is anywhere near saturation at this stage. Instead, deCODE's problems seem to stem from poor strategic decisions (or, more charitably, from long-term investments in R&D that are yet to bear fruit). Bear in mind that this is a company that has never actually made a quarterly profit, and has declared total losses of $600 million since it was founded in 1996. This quarterly report from September 2007 tells the story:

We incurred a net loss of $63.1 million and $62.2 million for the nine-months ended September 30, 2007 and 2006, respectively, and $85.5 million for the year ended December 31, 2006, and had an accumulated deficit of $598.8 million at September 30, 2007. We have never generated a profit and we have not generated revenues except for payments received in connection with our research and development collaborations with Roche, Merck and others, from contract services, Emerald BioSystems products and instruments, and under grants. [...] It may be several years before product revenues materialize, if they do at all. As a result, we expect to incur net losses for several years. If the time required to generate product revenues and achieve profitability is longer than we currently anticipate or the level of losses is greater than we currently anticipate, we may not be able to continue our operations.

I don't get the feeling that deCODE's fundamental problem is market saturation - it's just running out of money because it's failed to turn a huge investment in research into marketable items. But hey, I'm no market analyst, and I'd be very interested in hearing about this from experts (calling David Hamilton?).

Hsien finishes with an excellent point about the need for personal genetics companies to sell the wider public on the utility of their products:

In any case, while 23andMe and Knome focus on the rich, famous, and elite, there is a great need to show the general public how genetic testing of all types is relevant to their everyday lives. There aren’t enough millionaires like Dan Stoicescu to fund the entire personal genomics market. Until genetic testing is widely adopted for a variety of commercial uses by a greater segment of the consumer population, the pot of profits will not be big enough to share. In 2008, we will surely see companies drop out and others consolidate.

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Knome customer featured in NY Times

An article in the NY Times entitled "Gene Map Becomes a Luxury Item" introduces us to Dan Stoicescu, one of the first two customers to fork out $350,000 to get their genome sequenced by the personal genomics company Knome (pronounced "know-me" - get it?).

The article is well worth a read for anyone interested in the future of personal genomics, but one theme stands out for me:

Biologists have mixed feelings about the emergence of the genome as a luxury item. Some worry that what they have dubbed “genomic elitism” could sour the public on genetic research that has long promised better, individualized health care for all. But others see the boutique genome as something like a $20 million tourist voyage to space — a necessary rite of passage for technology that may soon be within the grasp of the rest of us.

I'm firmly in the second camp. In a previous post about Knome I noted that, "The willingness of wealthy early adopters to pay excessive amounts for untested technology is a big driver of progress" - in other words, Stoicescu and his fellow Knome customer are subsidising the costs of technology development that will eventually make genome sequencing cheaper for you and me.

Many new technologies start off as expensive yuppie toys, and rapidly tumble in price until they become accessible to the rest of the world. Worrying about "genomic elitism" is like someone back in 1981 worrying about "portable computer elitism". If a technology has broad appeal and utility - and in a few year's time, personal genomics will have both those things in spades - the price will come down quickly. You'll be chatting to your next-door neighbour about your kids' DRD4 genotypes before you know it.

Unfortunately for the early adopters, we currently know so little about the function of most genetic variants that their full sequence won't give them much more information than they could get from 23andMe or deCODEme, for 0.3% of the price. It's true that they're likely to find a few severe recessive disease variants, but these will have little or no effect on their own health, and are unlikely to affect their children (unless they're unfortunate enough to mate with someone who also carries a mutation in the same gene). There's also a low probability that they'll find something really nasty like a Huntington's disease mutation. But overall, the expected utility of this information is low - certainly not worth the $350,000 price tag, unless you're wealthy enough to not have to worry about that kind of money.

The true value of a genome sequence - identifying and deciphering the thousands of small changes that influence our risk of both rare and common diseases during our lifetime - won't come until we have complete sequences from hundreds of thousands of people, along with thorough medical information to find associations between variants and diseases (cue the Personal Genome Project). By that time, costs for full genome sequencing will be dramatically lower - hell, even poor scientists like me will be able to afford it!

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Google backs the Personal Genome Project

Bloomberg.com reports that Google has invested an unspecified amount in George Church's Personal Genome Project, which plans to sequence protein-coding regions from the genomes of 100,000 humans and link the sequence data with information on health and other traits (such as facial and body measurements). This is in line with Google's $3.9 million investment in 23andMe; this is a company that clearly sees the impact that analysing genetic variation will have on human health, and wants to position itself at the fore-front of that wave.

The Bloomberg article is well worth a read for various other useful snippets of information. For instance, I liked Church's argument for why the first participants in the PGP are willing to take the risk of freely sharing their genetic information with the rest of the world: "The payoff is an unobstructed view of the next revolution in medicine".

HT: Genome Technology Online

23andMe: give us information to "help future generations"

Esther Dyson, a director at 23andMe, has a new post on 23andMe's blog The Spittoon. Dyson acknowledges how little we currently know about the functional effects of most variable sites in our genome, and explains how 23andMe plans to address that issue:

To learn more, researchers need to collect thousands of genetic profiles – and the health data connected with each of them – to find correlations between the two. That leads to a second goal of 23andMe – to collect a large database of genetic information and then come back to you over time with invitations to provide specific health data and participate in research.

As David Hamilton has previously pointed out, the underlying business model of most of the current personal genomics companies is almost certainly not reliant on the money that customers pay for their genome scans (the profit margin on each scan is likely quite small, although I guess it helps to pay the bills). Instead, the plan is to aggregate genetic and trait data from customers and use it to find new genetic associations. These new associations can be fed back to customers, but they can also be used to create a data-set that might be of value to biotech and pharmaceutical companies. That's almost certainly where the personal genomics companies are hoping the real money is.

This plan has the potential to be a win for both customers and companies, as Dyson explains:

We’re not asking you to do this for purely altruistic reasons - either on our part or on yours. We’re a profit-seeking company, even though our founders and employees – and directors! – all share the vision of better understanding of everyone’s genomic make-up. As for you, the research results your data help produce could translate directly into benefits for you, or at least for your children, grandchildren and friends.

I've previously expressed my doubts about how useful the information generated by 23andMe will be, at least if they rely purely on self-reported trait data from online surveys (of course, they have other options). But perhaps I'm underestimating the power of incentives: customers want accurate new associations to be added to the 23andMe database to increase the value of their $1000 purchase, which might be enough to make them pay extra care to the information they put in themselves.

Of course, the ultimate would be a collaboration between 23andMe and Google's medical record storage service - access (with consent, of course) to both DNA samples and detailed health records from thousands of people would be a phenomenal engine for commercial success, and hopefully also a bonus to the research subjects. However, I suspect that the outraged screams from privacy advocates would be audible from space.

Ann Turner compares 23andMe and deCODEme

On the off chance that you haven't already seen it, check out genetic genealogist Ann Turner's extremely useful summary and comparison of the services offered by 23andMe and deCODEme, kindly hosted by Eye on DNA. The take-home message:

In the meantime, I think the tests are most suitable for those willing to explore the next frontier, with all its unknowns and with the possibility of less expensive tests coming online within the next few years. The cost-benefit analysis will be tricky for everyone, not just for my own little niche. But if you decide to proceed, I don’t think you can go wrong with either company.

For what it's worth, I think you're better off waiting a few years for large-scale sequencing to become affordable. But if you're really keen to be an early adopter, both companies have their pros and cons: 23andMe is altogether slicker and easier to use, while deCODEme offers almost twice the number of markers in their test (and is thus slightly more likely to have coverage for new disease markers that emerge over the next few years).

I suspect 23andMe's more intuitive interface would make them a better purchase for the lay user, while those with a bit of bioinformatics expertise might prefer deCODEme's denser SNP set for carrying out targeted data-mining (as Ann Turner is considering for identifying a hereditary deafness gene in her own family).

Knome signs up first two paying clients for whole-genome sequencing

Yesterday's press release from Knome has generated surprisingly little interest, but it's actually a pretty big deal: the company, in collaboration with the Beijing Genomics Institute, will be beginning whole-genome sequencing for its first two paying clients within the next few months. As the release says, these will be "the first individuals in the world to have their genome sequenced by a personal genomics firm".

The two clients have (wisely) chosen to remain anonymous at this stage. In return for around $350,000 in cold hard cash, they'll both be receiving "both sequencing and a comprehensive analysis from a team of leading geneticists, clinicians and bioinformaticians".

As I've noted before, the interpretation of whole-genome sequencing is complicated by the fact that no-one has a clue about the functional effects of most variations in the genome, and I wonder if these first clients will feel that they receive anywhere near enough useful information to warrant that hefty price tag.

It's true over the next few years there will be much better systems developed for predicting functional effects, and these customers' sequences will be ready and waiting to take advantage of this progress (whereas the genotyping data provided by the current crop of personal genomics companies will become increasingly obsolete). However, while this progress in interpretation is being made the cost of whole-genome sequencing will simultaneously be dropping by orders of magnitude. From a pure cost-benefit perspective the two customers would almost certainly be better off simply waiting for a few years, for a time when the cost of sequencing and the value generated by new analytical techniques start to meet half-way.

Of course, their loss is our gain. The willingness of wealthy early adopters to pay excessive amounts for untested technology is a big driver of progress: Knome (and everyone else keenly watching this experiment) will learn a great deal about the process of sequencing and interpreting genome sequences as a result.

And so, anonymous customers, I salute you: your willingness to spend large amounts of money for limited information will help to make my genome sequence cheaper and more useful, three to five years from now!

23andMe demo account goes live

23andMe has just announced free access to a demo account. So far I'm impressed by the slickness of the web interface (particularly compared to the demo account from deCODEme, so memorably labelled "underwhelming" by David Hamilton). The ancestry section in particular is easy to navigate and contains a wealth of information on different populations and geographical regions.

Well worth a look, particularly if you're considering actually shelling out for the full service.

Update 26/2/08: David Hamilton favourably reviews the 23andMe offering over at VentureBeat.