counsyl

One more step towards the end of recessive diseases

dgmacarthur — Thu, 13 Jan 2011 08:00:00 +0000

One more step towards the end of recessive diseases

In the last century infant mortality has declined precipitously in the Western world, thanks in large part to the development of antibiotics and vaccination. Yet as the suffering and death from infectious disease has reduced, the burden from genetic disease has become proportionately greater: currently around 20% of all infant deaths in developed countries are a result of inherited Mendelian (single-gene) disorders.

What can be done to reduce this burden? Increasingly sophisticated methods for detecting disease in embryos during pregnancy will help, and these have recently taken another step forward with the development of accurate, non-invasive methods based on analysing foetal DNA in the blood of pregnant mothers (an article in the BMJ this week demonstrates the feasibility of this approach for a non-Mendelian disease, Down syndrome; and the same group showed late last year that this approach can also be applied to effectively any known disease-causing mutation). Yet these approaches detect disease after pregnancy has already begun.

Disease mutations can also be detected in embryos prior to implantation, for prospective parents undergoing IVF. But IVF remains an expensive, arduous and invasive procedure, and thus a weapon of last resort for most parents-in-waiting; as Armand Leroi notes drily in an exceptional 2006 article in EMBO Reports: "nature has contrived a cheap, easy and enjoyable way to conceive a child; IVF is none of these things." (While Leroi goes on to argue that the challenges of IVF are less severe for young couples with no fertility problems, it still seems fairly implausible that this will become the default mode of reproduction in the near future.)

However, for some classes of Mendelian disease it's possible to move the screening one step back. Recessive diseases are insidious things. The mutations that cause them lurk undetected - each of us carry perhaps 5 to 10 of them - as their carriers are protected by the presence of a healthy second copy of the affected gene. These mutations can thus wait silently for generation after generation, until a carrier is unlucky enough to fall for someone who carries the same mutation, or another mutation in the same gene. The children of such a couple will each have a 25% chance of inheriting one damaged copy of the gene from each parent and thus developing the disease.

The ability of a recessive mutation to pass silently from generation to generation means that many children born with recessive diseases have no family history. And while certain marriage practices (notably serial first-cousin marriage) can dramatically increase the risk of having a child with a recessive disease, these diseases can also explode into appearance in families with no obvious risk factors.

However, the fact that both parents must carry mutations in the same gene to pass a recessive disease to their children raises the possibility of detecting risk before a couple has even conceived children. For instance, one could screen both members of a couple for a panel of known mutations, an approach currently offered by US company Counsyl (disclaimer: my wife and I both accepted free tests from Counsyl in 2009). However, while a panel containing all known Mendelian mutations could detect a substantial fraction of all genetic disease (Leroi again), it can never eliminate the risk, because many Mendelian mutations remain undiscovered. However, one could go one step further: rather than simply look for known mutations, one could examine the entire sequence of all genes known to be associated with Mendelian diseases, and thus identify new mutations lurking in the same gene.

In an article published today in Science Translational Medicine a group of US researchers describe a high-throughput approach for doing precisely that.

Rather than review the technical aspects of the paper in great detail, I'll just hit the main points I took from it:

The 448 genes selected for the screening panel are the product of walking a political tightrope. While the authors indicate that the marginal costs of adding extra sequence mean that the optimal cost-benefit ratio comes from including a very broad range of diseases, they have excluded diseases that might trigger controversy (such as deafness and adult-onset disorders).

The authors do a commendable job of comparing multiple technologies for capturing disease genes and for sequencing the captured DNA; the final product is a combination of Agilent SureSelect for sequence capture and Illumina HiSeq for sequencing.

This approach allowed them to detect ~95% of the genetic variants in their target genes with very high accuracy. In other words, they might miss around 5% of disease-causing mutations in these genes, but the ones they find are probably real.

Perhaps the single most important message from the paper, which I hope to expand on in a future post, is that disease mutations reported in the literature are depressingly enriched for false positives. The authors suggest that 27% of mutations in their samples that overlap with entries the largest database, the Human Gene Mutation Database, turned out to be the result of sequencing errors or mistakes in the literature (e.g. common polymorphisms that have been falsely reported to be disease-causing).

The researchers found that the 104 sequenced samples contained on average 2.8 known disease-causing mutations in the surveyed genes. This fits with expectations: each of us is likely walking around with 5-10 of these severe disease-causing variants in total, which we will only know about if (1) we get our genomes sequenced, or (2) we're unlucky enough to have children with a partner who carries mutations in the same gene.

The authors estimate the cost of their test at $378, which they note is "approximating that expended on treatment of severe recessive childhood disorders per U.S. live birth". In other words, offering this type of screen across the US population as a whole would be roughly cost-neutral from a healthcare stand-point, while simultaneously reducing the number of children dying from genetic diseases.

Given the plummeting costs of sequencing and the economies of scale, the cost-benefit ratio for this type of screening panel will continue to drop. In this context it seems inevitable that some form of sequencing approach will ultimately be implemented as routine for young parents-to-be.

That's not to say there aren't challenges ahead: obviously the current implementation misses ~5% of disease-causing mutations in the targeted genes (although this will improve with better sequence capture technology), and the panel of targeted genes needs to increase. But the largest obstacle that needs to be overcome is predicting the probability of disease causation for novel genetic variants uncovered by these screens: if two potential parents both carry rare protein-altering mutations in the same gene, but those mutations have never been seen in actual disease patients, what advice can we provide? Tools for predicting likely functional impact based on protein structure and evolutionary conservation are a start, but remain in their infancy; this is, I suspect, the challenge that needs to be faced up to by geneticists over the next five years.

Another key road-block is a social one: engineering the systems required to explain the results from these tests to large numbers of people, most of whom have very little understanding of genetics. The medical system is currently entirely unequipped to cope with an influx of this type of genetic data; yet cope it must, as the wave is coming fast.

Finally, the media coverage of this study has predictably stirred up the standard ethical and religious objections; these make for interesting dinner party conversation, but are largely irrelevant in any practical sense. Parents, as a group, will simply do whatever it takes to increase the probability that their children will be born healthy. Armand Leroi conveys this point well in the 2006 article mentioned above:

These abortions are eugenic in both intention and effect--that is, their purpose is to eliminate a genetically defective fetus and thus allow for a genetically superior child in a subsequent pregnancy. This is a harsh way of phrasing it; another way is to say that parents just want to have healthy children. Nevertheless, however it is phrased, the conclusion is starkly unavoidable: terminating the pregnancy of a genetically defective fetus is widespread. Moreover, because none of the countries mentioned above coerce parents into aborting deformed fetuses, these abortions--which number many thousands each year--are carried out at the request of the parents, or at least the mothers. This high number of so-called medical abortions shows that many people, in many parts of the world, consider the elimination of a genetically defective fetus to be morally acceptable.

Protests from ethicists and ministers may lead to some entertaining talk radio discussions, but ultimately the desire of parents for healthy children will sweep aside all objections (just as moral objections to tissue transplants and IVF were swept aside for similarly pragmatic reasons). In the face of this implacable tide I find it difficult to get too engaged in the moral debates on these issues; they just seem like a waste of time.

In closing: this is a commendable study, and offers a taste of what is to come. Carrier screening will be one of the first genomic technologies to really provide medical utility in a population health sense. It's important not to minimise the technical and logistical challenges ahead, but it seems inevitable that this approach will begin to be adopted on a population scale in the near future. And while noise and fury from critics on both the left and the right is similarly inevitable, the bottom line is simple: this technology will mean fewer children dying in pain, and all the moral outrage in the world won't drown that out.

dgmacarthur Thu, 01/13/2011 - 03:00

Tags

carrier testing

counsyl

disease genetics

genomic medicine

illumina

next-generation sequencing

pre-natal genetic diagnosis

re: what you point out as depressingly high false positive - in the screening community that's actually considered a good thing - you'd rather have false positives (which you can reconfirm by targeted sequencing/whatever) than false negatives.

Hi Jon,

In the specific "depressingly high" example in my post, the problem is that these are (mostly) artefacts in the literature rather than in your own experiment, so they're harder to untangle.

I can't help but wonder how many kids have been given a false diagnosis based on these artefacts; perhaps it's a small number, but I'm sure it's not zero.

Forgot to say: fair point about FPs vs FNs in screening (although obviously if the FP rate is way too high, or if you need to do an invasive assay for follow-up - as in Down syndrome - you're in trouble).

Yeah, the tolerance for FPs is more in the newborn screening arena rather than carrier screening.

Protests from ethicists and ministers may lead to some entertaining talk radio discussions, but ultimately the desire of parents for healthy children will sweep aside all objections (just as moral objections to tissue transplants and IVF were swept aside for similarly pragmatic reasons). In the face of this implacable tide I find it difficult to get too engaged in the moral debates on these issues; they just seem like a waste of time.

The excellent EMBO paper you cite ends in a much more nuanced way - that the morality of the issue is important, simply a scientist has no privileged contribution to make:

Some readers might find it peculiar that in this discussion of neo-eugenics, I have not considered the ethical or legal implications with which this subject is generally considered to be fraught. Although I do not doubt their importance, I simply have no particular knowledge of them. Peter Medawar put it best 40 years ago: âIf the termination of a pregnancy is now in question, scientific evidence might tell us that the chances of a defective birth are 100 percent, 50 percent, 25 percent, or perhaps unascertainable. The evidence is highly relevant to the decision, but the decision itself is not a scientific one, and I see no reason why scientists as such should be specially well-qualified to make itâ

I would assume that with so much allelic heterogeneity and the difficulty in separating pathogenic variants from benign variants at many loci, this approach is going to be a bit dicey for some time. In time, most of these ambiguities will be clarified and this analysis will be very useful.

Another key road-block is a social one: engineering the systems required to explain the results from these tests to large numbers of people, most of whom have very little understanding of genetics. The medical system is currently entirely unequipped to cope with an influx of this type of genetic data; yet cope it must, as the wave is coming fast.

You're right, but on the bright side I think that interpreting results for common multigenic diseases would be much more difficult for medical doctors. I believe this is a great step towards the end of recessive diseases, as you say. Regarding eugenics, the word frightens more than its meaning.

Hi Neil,

The excellent EMBO paper you cite ends in a much more nuanced way - that the morality of the issue is important, simply a scientist has no privileged contribution to make

I'm not saying the moral issues here aren't important in a metaphysical sense (although, like Leroi, I don't have the background to contribute usefully to that discussion), just that they'll have very little practical impact on whether or not these technologies are adopted. If you think that there are moral objections that will be sufficient to overcome the parental desire to have healthy children and thus halt adoption of carrier testing, however, I'd be very interested to hear your argument.

Hi Daniel

I suppose I see morality as a practical subject for all, rather than a topic just for the philosophers. However, I agree that there is no requirement to engage with any and everybody on a topic, especially if you can see that the answer is pre-judged.

As it is in this case.

In the UK, there is already a national antenatal screening programme looking at fetal abnormalities, and a newborn programme looking at "phenylketonuria (PKU), congenital hypothyroidism (CHT), sickle cell disease (SCD), cystic fibrosis (CF) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD)" i.e. already including some recessive disorders for which from-birth treatments are indicated - see http://www.screening.nhs.uk/policydb.php for a full list of all programmes considered.

Extension to carrier testing "merely" requires it to pass the usual screening criteria - http://www.screening.nhs.uk/criteria - the most relevant of which are:

4. If the carriers of a mutation are identified as a result of screening the natural history of people with this status should be understood, including the psychological implications.

9. If the test is for mutations the criteria used to select the subset of mutations to be covered by screening, if all possible mutations are not being tested, should be clearly set out.

14. There should be evidence that the complete screening programme (test, diagnostic procedures, treatment/ intervention) is clinically, socially and ethically acceptable to health professionals and the public.

15. The benefit from the screening programme should outweigh the physical and psychological harm (caused by the test, diagnostic procedures and treatment).

19. Adequate staffing and facilities for testing, diagnosis, treatment and programme management should be available prior to the commencement of the screening programme.

22. If screening is for a mutation the programme should be acceptable to people identified as carriers and to other family members.

I'm sure somewhere this is being put together as a proposal right now.

Hi Neil,

That last criterion is extremely interesting, as it could allow current disease patients to block the widespread adoption of testing to eliminate that disease. This seems like a pretty good example of a case where the desires of parents will clash with the suggestions of ethicists: from a parent's perspective, why should a current sufferer of a disease be able to prevent me from doing my best to have healthy children?

In addition, it's unclear to me whether you're suggesting that these criteria for providing an NHS-funded screening programme should also be extended to decisions about whether or not to permit a commercial entity from offering carrier screening to UK citizens. And if so, if the data aren't yet available to satisfy all of the criteria, should these tests be banned?

Daniel @10

That last criterion is extremely interesting, as it could allow current disease patients to block the widespread adoption of testing to eliminate that disease.

You mean for things that some think of as a disease and many do not? - like:

"Deaf demand right to designer deaf children"
http://www.timesonline.co.uk/tol/news/uk/health/article3087367.ece

I think the section may have arisen from the early history of compulsory sickle cell testing in the US - this from http://www.scienceprogress.org/2008/05/a-brief-history-of-genetic-testi…

Sickle cell testing between 1970 and 1972 was mandatory in 12 states and targeted African-Americans. Misunderstanding was rampant, perhaps because the term âsickle cell traitâ for carriers suggested that their condition was somehow visible. What they carried was stigma. At the time, the disease could not be prevented, tested for before birth, or treated. So why identify carriers?

This seems like a pretty good example of a case where the desires of parents will clash with the suggestions of ethicists: from a parent's perspective, why should a current sufferer of a disease be able to prevent me from doing my best to have healthy children?

I think this is saying no such thing - merely that the NHS will not attempt to roll out a national program if there is serious opposition to it.

No. Like many here, I believe that genetic testing should be registered and regulated to keep the bottom-feeders out of the market, but I was mainly responding to your suggestion that carrier testing would become "routine" once the price came down and the utility goes up - it needs more than that.

And if so, if the data aren't yet available to satisfy all of the criteria, should these tests be banned?

In my view, no. What we're facing is a lack of data, not ethical roadblocks.

New FireFox plugin for 23andMe customers [Genetic Future]

sb admin — Tue, 11 Jan 2011 11:00:00 +0000

New FireFox plugin for 23andMe customers [Genetic Future]

Software company 5AM Solutions has just launched a neat little FireFox plug-in for customers of consumer genomics company 23andMe.

The idea is very simple:

Download your raw data from 23andMe (or use one of the files from me or my colleagues at Genomes Unzipped);
Install the plug-in from here and point it to your 23andMe data;
Browse to a website discussing one of the genetic variants included on the 23andMe chip, and you'll see highlights around the rsID of any variant on the page (rsIDs are unique codes assigned by dbSNP to most of the common variants targeted by personal genomics companies);
Mouse over the rsID and your own genotype for that SNP will appear.

For any 23andMe user who's ever come across a variant on PubMed and wondered what their own genotype was, then gone through the process of logging into 23andMe and checking, the value of this tool is immediately obvious.

Here's a screenshot using my own data:

SNPtips creator Andrew Evans has a blog post up explaining the rationale behind the project. I spoke to Evans by email earlier this week, and he told me that future plans for the tool include development for Chrome, extension to data-sets from other companies such as deCODEme and Navigenics, and provision for viewing data from multiple individuals (which will be useful for those with multiple genotyped family members, or for groups like Genomes Unzipped).

As more people gain access to increasingly more comprehensive information about their own genome, online tools will become essential for navigating the data rapids. This is a small but very useful step in that direction.

sb admin Tue, 01/11/2011 - 06:00

Tags

next-generation sequencing

pre-natal genetic diagnosis

Why you CAN have your $1000 genome - so long as you learn what to do with it [Genetic Future]

sb admin — Fri, 07 Jan 2011 09:10:00 +0000

Why you CAN have your $1000 genome - so long as you learn what to do with it [Genetic Future]

As part of his Gene Week celebration over at Forbes, Matthew Herper has a provocative post titled "Why you can't have your $1000 genome". In this post I'll explain why, while Herper's pessimism is absolutely justified for genomes produced in a medical setting, I'm confident that I'll be obtaining my own near-$1000 genome in the not-too-distant future.

Matt's underlying argument is that while sequencing costs will continue to drop, obtaining a complete genome sequence that is sufficiently accurate for medical interpretation will require additional expenses (increased sequence coverage to ensure accuracy, all of the computation required to stitch the raw data into a useable form, and paying doctors to perform the interpretation) that will keep the cost of medical sequencing well above the arbimagical US$1,000 threshold. Instead, Herper argues, we will likely see medical-grade genomes stay above $10,000, or at least above the $2,000 currently forked out for MRI scans.

There's certainly some depressing truth here. I believe Herper is right that if you intend to access your genome sequence via a traditional medical route, it will certainly cost more than $1000 for the foreseeable future - if indeed you can get access to it at all, which is by no means guaranteed. The costs of clinical sequencing will include even more overheads than Herper notes in his short post: for instance, even as the accuracy of high-throughput sequencing technology improves, there will still be a need for variants with major medical impact to be independently validated in clinical labs, and custom assays don't come cheap.

However, many of these extra costs of clinical sequencing will be further inflated by regulatory demands (at least some of which will be arbitrary and pointless), and many will only apply if you obtain your genome through the medical system. Individuals with the motivation to seek alternative routes will be able to obtain a perfectly serviceable genome sequence at a substantially lower price: they'll have to be cautious in how they interpret the results, of course (although, importantly, this is also true of a medical test), but it will be possible to obtain substantial and potentially extremely useful information from your own genome without having to pass through the clinical toll-booths.

The key obstacle will be the development of cheap (or free), intuitive tools for annotating large-scale genetic information. Purchasing the sequencing itself will be trivial: even if the FDA succeeds in crushing innovation in direct-to-consumer genetic testing in the US, there will be plenty of companies abroad (especially in East Asia) willing to convert a mailed saliva sample into an assembled genome sequence. What the individual needs to do with that sequence is to (1) validate that the sequence they receive is in fact their own genome; (2) extract medically useful variants; (3) confirm that these variants are real; and (4) figure out how that information should be used to make health and lifestyle decisions.

Only one of these steps (the final one) will require direct consultation with the medical profession. The first will require comparing the sequence with independent genetic data (such as a genome scan from a company like 23andMe) to check that the two match the same individual (i.e. you), and also to provide an indicator of the global quality of the sequence. The second step is currently extremely challenging, but we can expect tremendous innovation in genome interpretation software and databases of functional variants over the next few years that will gradually simplify and improve this process. The third step will require sending another DNA sample to a company that does affordable, custom assays of a small number of genetic regions of interest using an independent technology. And the final step will involve discussing the results with everyone who might be able to tell you something useful about them, including your family and your doctor.

None of this is simple, but it will become easier with time. As the retail costs of sequencing drops, a substantial niche will develop for innovators providing affordable, intuitive, accurate interpretation tools (embryonic versions already exist: see, for instance, Promethease or Enlis Genomics). Open-source academic software built for large-scale sequencing projects will be adapted for use by non-specialists. The increasing availability of large-scale computing power (for instance, via Amazon EC2), coupled with this intuitive software, will make even compute-intensive analyses available to the educated, motivated lay-person. (Incidentally, tracking and fostering the development of these tools is one of the motivations behind the Genomes Unzipped project - and you'll hear more about our plans in this area in 2011).

Done carefully, there's no reason why a DIY genome couldn't be every bit as useful (or indeed as useless, in many cases) as one obtained through the doctor-as-gatekeeper route. As Dan Vorhaus argued after last year's sample mix-up at 23andMe, it is likely that clever DIY genomicists will be better at picking up certain kinds of errors (such as sample swaps) than clinical labs would. In terms of accuracy, while retail genomes may not reach the same quality standards as those generated by clinical labs, increased competition and innovation in the direct-to-consumer space will mean they're unlikely to lag too far behind - and judicious use of independent validation of important variants would in most cases raise the reliability to a level is equivalent to, or even higher than, a medical-grade test. Of course, for the very small number of genetic variants per genome that might require urgent, serious action - such as BRCA1 breast cancer-associated mutations - individuals can always fork out for a clinical test.

What proportion of people will take this DIY route? This isn't for everyone. Those wealthy enough to blithely fork out $10,000 for a medical genome interpretation, or sufficiently unwell to be able to convince their insurance company or public health system to pay for it, will by and large simply take the expensive medical route. Of the remainder, relatively few people will be sufficiently motivated to develop the background knowledge required to make sense of their genome, even if the analysis software is relatively intuitive. But for the non-trivial fraction of the population who want to know about their genomes, but don't want to pay the inflated costs associated with medical-grade sequencing - and I know this is a category that many readers of Genetic Future fall into - this will be an attractive and feasible option.

In addition, there will be advantages to the DIY approach beyond the lower cost. People who actively engage in the process of constructing useful information from raw sequence data - regardless of how intuitive the software is for doing it - will automatically learn important lessons about the nature of genetics (just as anyone who has given more than a casual glance at their own 23andMe profile has automatically learnt something important about the probabilistic nature of genetic risk factors for common diseases). They will also have opportunities to ask and answer fascinating questions that would be irrelevant in a purely medical consultation about your genome: for instance, what does your genetic information tell you about your ancestry?

They'll be able to ask these questions because they will own the data. How easy do you think it will be to obtain your raw genome sequence from your doctor to use to satisfy your own curiosity? How many forms and disclaimers will you need to sign? How many times will you need to listen to someone tell you that the data files are just too large, that the formats are inaccessible to lay-people, that your request is extremely unusual and will need to be considered for months by a hospital committee in the name of "health data privacy"? Anyone who has ever tried to get access to their own medical records will know how tedious and shrouded in unnecessary mystery this process can be; imagine how much larger the obstacles will loom when the system has the additional excuse of large, complex file formats to throw in your path.

Importantly, your genome is just one contributor to your present and future health. DIY genomics will, I hope, be part of a larger ongoing trend towards individuals taking greater personal responsibility for tracking and maintaining their own wellness - a task, incidentally, which modern healthcare systems are spectacularly ill-equipped to perform, something that seems unlikely to change substantively in the near future. As Western populations age, this broader shift of responsibility will be essential for healthcare systems to survive.

But I digress. My point here is simply this: Herper is perfectly correct that the overheads imposed (for a mixture of valid and arbitrary reasons) by medical-grade testing will ensure that clinical genomes remain expensive. But for those of us willing to learn the skills required to go outside the system, the $1000 genome is rapidly approaching. We just need to be ready to make the most of what it contains - and to reap the benefits of accessing that information as an active, engaged participant rather than a passive recipient.

sb admin Fri, 01/07/2011 - 04:10

Categories

Free Thought

Bioscience Resource Project critique of modern genomics: a missed opportunity [Genetic Future]

sb admin — Wed, 15 Dec 2010 06:15:00 +0000

Bioscience Resource Project critique of modern genomics: a missed opportunity [Genetic Future]

Late last week I stumbled across a press release with an attention-grabbing headline ("The Causes of Common Diseases are Not Genetic Concludes a New Analysis") linking to a lengthy blog post at the Bioscience Resource Project, a website devoted to food and agriculture. The post, written by two plant geneticists, plays a tune that will be familiar to anyone who has encountered the rhetoric of GeneWatch UK: basically, modern genomics is pure hype perpetuated by scientists seeking grant money and corporations seeking to absolve themselves of responsibility for environmental disasters.

The post is long, but its core argument can be summarised as follows:

Genome-wide association studies (GWAS) have failed to find variants explaining much of the risk of common diseases like type 2 diabetes;
The potential hiding places postulated for the remaining "missing heritability" are implausible;
Many epidemiological studies have shown a major role for environmental factors in determining disease risk;
Studies estimating the proportion of disease risk determined by genetics using twin pairs are flawed;
Both corporations and medical researchers have incentives to prop up the notion that common diseases have genetic causes;
Therefore, the notion of major genetic causation for common diseases is a fallacy, and we should stop looking for disease genes in favour of investing in beneficial environmental changes.

These claims would be fascinating, if true. However, while the article makes some (scattered) valid points, its central claim (that the results of GWAS suggest that genetics plays little or no role in the causation of common diseases) is entirely false, and the authors rely on a combination of distortions and statistical misunderstandings to make their case.

Unfortunately the article has not simply lapsed back into the internet obscurity it deserved: over the weekend a link to the article was posted on Twitter by popular author Michael Pollan, bringing it to the attention of his ~40,000 followers. Pollan's tweet and the cheer-leading responses from his followers were subsequently picked up and blasted over at OpenHelix, leading to an exchange with one of the authors in the comments. The article was also criticised for a schoolboy statistical error by Luke Jostins, but received a qualified positive review from Mike the Mad Biologist.

So, let's take a closer look at how well the some of the claims in the article stand up.

Why was the post written?

The article itself is written in a reasonably neutral tone, which could easily fool the casual reader without a solid background in genetics (like, perhaps, Michael Pollan) into seeing it as a dispassionate critique of the field. However, it's important to read the post in the appropriate context.

In a comment over at the Huffington Post found by Keith Grimaldi, one of the authors explains the key messages and motivations of his analysis:

We have just reported that genetics now demonstratÂes that genes cannot be the cause of common diseases:

http://wwwÂ.biosciencÂeresource.Âorg/commenÂtaries/artÂicle.php?iÂd=46

That means environmenÂt must be the entire cause of ill health, i.e. junk food, pollution, lack of exercise, etc. The reason we wrote an article about human genetics (when we are a food and agriculturÂe website) is that we believe that if people live right, agriculturÂe and therefore the planet will more or less fix itself. [my emphasis]

This quote is illuminating in a number of ways. Firstly, it shows that there is no nuance in this argument: the authors aren't attempting to argue that genes play a smaller role in common disease than geneticists expected, but rather that genetics plays no role whatsoever.

Secondly, it reveals the motivations behind the post: the authors have assembled this critique, despite their acknowledged lack of expertise in the field, because they want to encourage a greater focus on behavioural and economic changes to bring large-scale environmental benefits. A noble cause, to be sure, but not one that necessarily encourages them to take a balanced approach to the discussion.

I don't mean to discount the post itself on the basis of its authors' motivations, but I do think it is important to read the piece in this context.

OK - on to some of the specific claims made in the piece.

Possible explanations for the missing heritability are post hoc and implausible

The authors claim:

A problem for all these hypotheses, however, is that anyone wishing to take them seriously needs to consider one important question. How likely is it that a quantity of genetic variation that could only be called enormous (i.e. more than 90-95% of that for 80 human diseases) is all hiding in what until now had been considered genetically unlikely places? In other words, they all require the science of genetics to be turned on its head. [italics in original]

This is complete nonsense. Indeed, the authors' question should be turned on its head: How likely is it that a technology that we know is only well-powered to find risk-associated variants that are common and have reasonable effect sizes will have found all - or even most - of the variants underlying common disease risk? If the answer to that question is "not very likely" - as it clearly is - then the authors' argument falls apart. Genome-wide association studies (GWAS) were not conducted because scientists expected them to find every disease-associated variant, but because they were a place to start with the technology that was available; the fact that a large fraction of the heritable risk remains undiscovered is not a sound reason to doubt that risk was heritable in the first place.

Some fraction of the missing heritability for complex diseases may turn out to lie in exotic candidates such as epigenetic inheritance or heritable variation in microflora, but these aren't yet required explanations. There are also perfectly mundane locations that haven't yet been explored by modern genomics, and would require absolutely zero changes to "the science of genetics" to investigate. For instance, genome-wide association studies (GWAS) conducted to date have been seriously under-powered to detect risk variants at low frequency (less than 5%) in the population, as well as common variants with individually very small effects on disease risk - yet there's no reason not to expect an appreciable fraction of the population variance in disease risk to fall into these categories. Or, again, are we expected to believe that the distribution of allele frequencies and effect sizes for disease risk variants falls entirely within the range for which GWAS conducted to date have been 100% powered to detect them?

We haven't even begun to make the most of risk variants we have already uncovered. GWAS are capable of flagging up a region of the genome linked to a disease, but typically don't immediately identify the precise genetic change responsible for that association. More detailed analyses of risk-associated regions (known as fine-mapping) allow researchers to zoom in on variants that are more tightly linked with the underlying causal change - and this alone can substantially increase the fraction of variance explained.

Variants discovered by GWAS are useless

The authors argue:

For each disease, even if a person was born with every known 'bad' (or 'good') genetic variant, which is statistically highly unlikely, their probability of contracting the disease would still only be minimally altered from the average.

Erm, no. Luke Jostins has a very handy post showing the distribution of risk prediction scores for individuals with different combinations of genetic variants associated with three common diseases: type 1 diabetes, type 2 diabetes, and Crohn's disease. Given he'd gone to all the work of collating these distributions, I asked him to do precisely the analysis the post authors describe here, and compare the predicted risk of individuals with all possible risk variants to the population average.

Here are the results for people with the average risk vs those with the highest number of risk variants:

Type 2 diabetes: 19.6% vs 41.3%

Type 1 diabetes: 1% vs 65%

Crohn's disease: 0.4% vs 99.6%

This analysis includes only variants identified by GWAS, but it's also based on a somewhat out-of-date catalogue of variants - so updating the results would increase this spread slightly further. [Explanation above edited to correct minor error in original version, which stated numbers were for lowest vs highest risk rather than average vs highest risk.]

Do the authors genuinely believe that the difference between 0.4% and 99.6% risk represents "minimal alteration", or have they just not bothered to actually look into these numbers themselves?

Strong environmental effects on disease risk argue against strong genetic effects

This argument pops up in a number of places in the article. For instance, the authors point out the apparent contradiction between twin studies suggesting that the risk of myopia is 80% heritable, whereas individuals moving from non-Western to Western countries can go from a prevalence of myopia of 0% to 80%. How can these two figures be reconciled?

The answer is that heritability is a number that applies to a specific population within a specific environment. Within white Europeans living in Western countries, who face a reasonably uniform set of environmental risk factors, around 80% of the risk of myopia is genetic. That number will obviously not apply to a population in which some individuals are moving from a low-risk to a high-risk environment, in whom the majority of the risk is primarily determined by that massive environmental difference. However, importantly, that doesn't mean the heritability estimate isn't correct for white Europeans: it just means that it shouldn't be extrapolated to other populations subject to different combinations of genetic and environmental risk factors.

There is no contradiction here, just a misunderstanding of the concept of heritability. The authors' misunderstanding should remind us of the caution that needs to be applied when thinking about heritability, and also that the existence of strong genetic predispositions to common diseases doesn't mean that environmental interventions can't be extremely effective. However, it's not a valid critique of the heritability estimates generated for common diseases.

The evidence for disease heritability from twin studies is flawed

The authors claim:

Studies of human twins estimate heritability (h²) by calculating disease incidence in monozygotic (genetically identical) twins versus dizygotic (fraternal) twins (who share 50% of their DNA). If monozygotic twin pairs share disorders more frequently than do dizygotic twins, it is presumed that a genetic factor must be involved. A problem arises, however, when the number resulting from this calculation is considered to be an estimate of the relative contribution of genes and environment over the whole population (and environment) from which the twins were selected. This is because the measurements are done in a series of pairwise comparisons, meaning that only the variation within each twin pair is actually being measured. Consequently, the method implicitly defines as environment only the difference within each twin pair. Since each twin pair normally shares location, parenting styles, food, schooling, etc., much of the environmental variability that exists between individuals in the wider population is de facto excluded from the analysis. In other words, heritability (h²), when calculated this way, fails to adequately incorporate environmental variation and inflates the relative importance of genes. [my emphasis]

As Luke Jostins has already explained at length over at Genomes Unzipped, this criticism is based entirely on a statistical misunderstanding of the methodology behind heritability studies. In fact, the sentence highlighted in bold above is completely wrong: twin-based heritability estimates use between-family variability, not within-family variability, to estimate the proportion of variation that is due to the environment. This misunderstanding completely undermines their argument against heritability estimates.

As Luke notes, there are valid reasons to be cautious about heritability estimates from twin studies - but this isn't one of them.

What this piece could have been

Mike the Mad Biologist has a post about this article, in which he describes it as having "good and bad points". I should also be charitable: although the central argument of the post (that results from GWAS suggest that genetic factors have little or no role in common disease) is completely wrong, there are valid criticisms of the excessive value that is sometimes placed on genetic versus environmental explanations of morbidity.

Stripping away the conspiracy-mongering and accusations of genetic determinism among geneticists (seriously, how can anyone working on complex diseases be a genetic determinist?), there are some nuggets of truth in the article's discussion:

The last fifteen years, coinciding with the rise of medical genetics, have seen unprecedented sums of money directed at medical research. At the same time, research on pollution, nutrition and epidemiology has not benefited in any comparable way.

[...]

This same mindset is accurately reflected in the media where even strong environmental links to disease often receive little attention, while speculative genetic associations can be front page news.

Even as a direct beneficiary of money thrown at medical genetics over the last five years, and someone who blogs entirely about news in the genetic domain, I freely acknowledge that these criticisms have merit. Genetic dissection of common disease is valuable, and will be (and indeed already has been) fruitful in generating new therapies, but it is nonetheless true that research into environmental risk factors and interventions to minimise morbidity is woefully under-funded and under-reported relative to its potential benefit.

This article could thus have been a considered, balanced and valuable critique of the imbalance in funding between research into the genetic and environmental contributors to common disease. Instead, the authors have undermined their argument by wandering into territory they don't understand, and taking an extreme position that is inconsistent with the available evidence. Perhaps they felt that polarising the debate was the only way to get attention - and indeed that approach seems to have worked - but that has come at the cost of destroying the credibility of their message. This was a missed opportunity.

sb admin Wed, 12/15/2010 - 01:15

Genomes Unzipped reader survey [Genetic Future]

sb admin — Fri, 03 Dec 2010 08:45:00 +0000

Genomes Unzipped reader survey [Genetic Future]

A reminder to anyone who reads my other blog Genomes Unzipped that we have a reader survey underway there now, which includes some questions about genetic testing experiences and attitudes towards genetics. We're closing the survey to responses this weekend, so if you're an Unzipped reader but haven't had a chance to fill in the survey, please do so now.

sb admin Fri, 12/03/2010 - 03:45

News from 23andMe: a bigger chip, a new subscription model and another discount drive [Genetic Future]

sb admin — Wed, 24 Nov 2010 07:45:00 +0000

News from 23andMe: a bigger chip, a new subscription model and another discount drive [Genetic Future]

Update 30/11/10: 23andMe has extended their 80% discount until Christmas, without a need for a discount code.

Personal genomics company 23andMe has made some fairly major announcements this week: a brand new chip, a new product strategy (including a monthly subscription fee), and yet another discount push. What do these changes mean for existing and new customers?

The new chip

23andMe's new v3 chip is a substantial improvement over the v2 chip that most current customers were run on (the v2 was introduced back in September 2008). Firstly, the v3 chip includes nearly double the number of markers across the genome, meaning that it is able to "tag" a larger fraction of common genetic variants ("tagging" means that a marker on the chip is sufficiently highly correlated with other markers that it can be used to make a reasonable guess about someone's sequence at those other markers). Secondly, the chip now includes additional custom markers targeting specific variants that the company thinks will be of interest to its customers.

The technical details: the v3 chip is based on Illumina's HumanOmniExpress platform, which includes 733,202 genome-wide markers. The company has also added around 200,000 custom markers to the chip (vs ~30,000 on the v2 chip). We don't yet have full details on what those custom markers are, but there's a summary of the improvements over the v2 chip in the press release:

Increased coverage of drug metabolizing enzymes and transporters (DMET) as well as other genes associated with response to various drugs.
Increased coverage of gene markers associated with Cystic Fibrosis and other Mendelian diseases such as Tay-Sachs.
Denser coverage of the Human Leukocyte Antigen region, which contains genes related to many autoimmune conditions.

Deeper coverage of the HLA is particularly welcome - variants in this region are very strongly associated with many different complex human diseases (including virtually every auto-immune disease), and the v2 chip was missing several crucial markers.

The addition of more rare variants associated with Mendelian diseases like cystic fibrosis is entirely unsurprising, but the devil will be in the details: in the arena of carrier testing 23andMe is up against the extremely thorough and experimentally validated platform offered by pre-conception screening company Counsyl. It will be very interesting to see the degree to which 23andMe focuses on the carrier testing angle in their marketing of the v3.

More power for imputation

From the perspective of those of us simply interested in squeezing as much information as possible out of our genetic data, the v3 chip is a welcome arrival. The additional markers present on the chip will substantially improve the power of genotype imputation - that is, making a "best guess" of our sequence at markers not present on the chip using information from tagging variants.

The HumanOmniExpress platform has some decent power here: in European and East Asian populations, 60-70% of all of the SNPs with a frequency above 5% found in the 1000 Genomes pilot project are tagged by a marker on the chip (in this context, "tagged" means "has a correlation of 80% or greater"). In effect, that means that being analysed at the one million markers on this chip allows you to make a decent inference of your sequence at around another 4.5 million other positions in your genome.

At the recent American Society of Human Genetics meeting, 23andMe presenter David Hinds suggested that the medium-term future for 23andMe rested not in moving to sequencing, but rather on expanding the role of genotype imputation. The new chip will certainly help with that. However, it's worth emphasising that imputation is not a replacement for sequencing: it is only accurate for markers that are reasonably common in the population, meaning that it will miss most of the rare genetic variants present in your genome.

However, improved imputation with the extra markers on the v3 chip will mean that 23andMe should be able to do a decent job of predicting customer genotypes at the positions we currently know the most about - those arising from genome-wide association studies of common, complex diseases. I expect that many customers will see changes to their disease risk profiles as a result of the move to the new chip.

Over at Genomes Unzipped, we've already been looking at various approaches to imputation from our 23andMe v2 data, and we'll put a post together soon looking at how this will improve with content from the v3 chip.

The new product strategy

There are two interesting things that 23andMe has done with the new product line: firstly, it has reversed the transient division of its products into separate Health and Ancestry components; and it has introduced a subscription model in which customers pay $5/month for updates to their account as new research findings become available (previously, customers paid a flat purchase fee and were then entitled to free updates).

The recombining of the Health and Ancestry products into a single Complete package is an extremely interesting move. As Dan Vorhaus notes, the previous separation of the two product lines was plausibly interpreted as a way for the company to pre-empt the possibility of a regulatory crackdown by the FDA: if regulators hammered the company's ability to offer health-relevant tests directly to consumers, 23andMe could easily switch to its Ancestry product to maintain a revenue stream.

In the currently uncertain regulatory environment, the decision to reverse this division is an unexpected one. It certainly appears that 23andMe - flush with cash following a successful $22M funding round - is somewhat more confident than I am about the regulatory future for health-relevant genetic tests; I hope that confidence turns out to be warranted.

Subscription fees: good for customers

The decision to add a subscription fee may prove unpopular with customers (and has already received a qualified thumbs down from blogger Dienekes, albeit for perfectly sensible reasons). However, a business model based on providing continuous product updates that customers don't pay for has never really looked like a viable long-term business model.

I personally see a subscription model as a positive move: it provides a steadier revenue stream for personal genomics companies, which means less focus on splashy discount drives. It also provides more of a financial incentive for the company to improve the ongoing experience of customers: under the current deal customers are locked in for the first 12 months, but after that 23andMe will need to convince them that it's worth continuing to pay for additional content and features.

Other personal genomics companies (e.g. Navigenics) have long relied on some form of a subscription model, but typically at a higher cost. I think 23andMe is hitting a pretty reasonable price point here: I suspect $60/year would be seen by most customers as a fair price.

OMG discount!

That doesn't mean that 23andMe has abandoned the discount drive approach just yet, of course: they're currently offering v3 kits for just $99 (vs the retail price of $499), which must be purchased along with the previously mentioned 12-month subscription fee of $60. Non-US customers can also expect a ~$70 postage fee, based on comments on Twitter.

Anyone who missed out on the DNA Day sale and is keen to take advantage of the v3 content would be well-advised to get in quickly. The discount code is B84YAG.

sb admin Wed, 11/24/2010 - 02:45

Categories

Social Sciences

Why I'm releasing my genetic data online [Genetic Future]

sb admin — Tue, 12 Oct 2010 06:45:00 +0000

Why I'm releasing my genetic data online [Genetic Future]

Back in June I launched a new blog, Genomes Unzipped, together with a group of colleagues and friends with expertise in various areas of genetics. At the time I made a rather cryptic comment about "planning much bigger things for the site over the next few months".

Today I announced what I meant by that: from today, all of the 12 members of Genomes Unzipped - including my wife and I - will be releasing their own results from a variety of genetic tests, online, for anyone to access. Initially those results consist of data from one company (23andMe) for all 12 members; deCODEme for one member; and Counsyl for two of us (my wife and I). As the project proceeds, we plan to obtain and release the results from a far wider range of genetic tests, up to and including complete genome sequences.

In all, the group is currently releasing over 7 million pieces of genetic data mined from our own genomes. Anyone can download the data in raw form, or view it on a custom browser that two of the group assembled using the open-source JBrowse software. Already the data is being used: blogger Dienekes yesterday published an analysis of our ancestry using his own program, EURO-DNA-CALC.

We have plenty more planned over the next few weeks, including discussion of the ethical issues associated with releasing data publicly, especially given the potential impact on family members. We'll also be presenting analyses of our own data: many of us are active researchers in genetics, and relish the opportunity to apply our research tools to our own genomes. We'll be releasing software code allowing others to run the same analyses on their own data.

So, why on Earth are we doing this?

I summarised some of the key motivations for members of the group in my Unzipped announcement post:

we want to share the results of scientific analysis of our own genomes, and as proponents of open data access most of us believe that doing good science means releasing complete data for others to investigate;
we hope that releasing our data publicly will help to guide useful discussions about genetic privacy and the benefits, risks and limitations of genetic information in general;
many of us believe that the ideal resource for genetic research is large open-access, non-anonymous research databases such as the Personal Genome Project, and that sharing linked genetic and trait information openly with the wider community is a public good - and we hope that our own experiences will encourage others to participate in open research projects;
we all believe that many of the fears expressed about the dangers of genetic information are exaggerated, and see this project as an opportunity to have a constructive public discussion about the truth behind these fears;
given the ease with which a dedicated snoop could obtain genetic information surreptitiously (via shed skin, hair or saliva, for instance), some of us argue that the whole notion of genetic privacy is illusory anyway - while releasing our data online makes it easier for people to get hold of it, this is a difference of degree rather than kind.

I wanted to spend a bit of time here expanding on that third point, as this is probably my own primary motivation for engaging in the project.

Any researcher working in genetics or genomics will be all too familiar with the cumbersome bureaucratic obstacles associated with subject privacy and anonymity. Under the traditional research model subject anonymity and data privacy must be protected fiercely, and that leads to substantial hurdles in two key areas: firstly, data sharing between researchers is hindered by the need to ensure that data privacy is maintained; and secondly, layers of protection on subject anonymity mean it is extremely difficult to return research results to participants, even when those results might have health implications.

This is not to say that huge advances in data access have not been made over the last decade, particularly in the field of genomics. Both individual researchers and funding bodies (notably the Wellcome Trust and NIH) have done a commendable job of ensuring that many large genomics data-sets are made available to other researchers through large databases and data access agreements.

However, can we go further? Researchers such as George Church advocate a bold alternative model: recruit research participants who are willing to share their data completely openly with the world. Find large enough numbers of people willing to sacrifice their privacy for public good, and you suddenly have an amazingly powerful resource: a data-set that can be analysed by any researcher in the world with access to the internet, including participants who can play an active role in the research process.

It can't be emphasised enough just how powerful such a resource would be. Right now, virtually all human genetic and medical data is effectively locked away behind tight consent agreements. That means a given data-set only has a certain number of eyes passing over it, with a restricted circle of expertise; one cohort's data might contain valuable insights into the mechanisms by which cholesterol affects heart disease, but if the researchers holding the keys are eye specialists those will probably never be uncovered.

Science moves fastest when people from diverse backgrounds are allowed access to rich data-sets. The closer we hew to the traditional model of tightly restricted access to human data, the slower we will uncover the associations we need to move into the era of personalised, evidence-based healthcare.

Are there enough people in the world willing to forego their privacy in the name of science? That remains to be seen, but flagship studies like the Personal Genome Project - which seeks to recruit 100,000 volunteers willing to share their genomes and clinical data with the world - are already suggesting that this number is far higher than many would have expected. However, visceral opposition to the idea of releasing such information - based often on an exaggerated sense of the power of genetic data, or its potential for abuse - continue to hold sway over the vast majority of the public.

We're under no illusions here: the data from the 12 of us in Genomes Unzipped aren't in and of themselves of tremendous scientific value. However, if we can get people starting to think about the genuine public good that can be achieved by sharing their data with science, and to weigh that good against a realistic sense of the potential harms, then the project has been a success.

Edited 13/10/2010 to clarify that major progress has been made in data-sharing agreements over the last decade, especially in genomics - I apologise to anyone who interpreted my views as minimising the work that has been done in this area.

sb admin Tue, 10/12/2010 - 02:45

Categories

Medicine

Where to next for personal genomics?

dgmacarthur — Thu, 20 May 2010 18:35:00 +0000

Where to next for personal genomics?

The brief Golden Age of direct-to-consumer genetic testing - in which people could freely gain access to their own genetic information without a doctor's permission - may be about to draw to a close. In a dramatic week, announcements of investigations into direct-to-consumer genetic testing companies by both the FDA and the US Congress have sent the personal genomics industry into a spin, and it is still impossible to say exactly which way it will be pointing once the confusion passes.

I've been frustratingly unable to find the time to cover the developments as they happened due to other commitments - but fortunately they have been extremely ably covered elsewhere, notably by Dan Vorhaus over at Genomics Law Report and Kirell Lakhman at GenomeWeb.

Here's a high-level summary for those who haven't been following closely:

On May 11, direct-to-consumer genetic testing company Pathway Genomics announced that it would be partnering with drugstore chain Walgreens to offer its genetic testing kits on the shelves of Walgreens' 7,500 stores.
The same day, the director of the FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, Alberto Gutierrez, was quoted as follows in the Washington Post:

"We think this would be an illegally marketed device if they proceed [...] They are making medical claims. We don't know whether the test works and whether patients are taking actions that could put them in jeopardy based on the test."
Two days after the Pathway announcement, and following a letter from the FDA to Pathway, both Walgreens and rival CVS Caremark, who had also apparently been planning to stock the kits, decided to drop the idea of offering Pathway's product in their stores.
Yesterday Dan Vorhaus broke the news of a newly-launched Congress investigation into direct-to-consumer genetic testing sparked off by the Pathway controversy (the announcement cites "recent reports that at least one of the companies is seeking to sell personal genetic testing kits in retail locations, despite concern from the scientific community regarding the accuracy of test results").

As always, the best place to go for detailed legal analysis of this ongoing furore is the Genomics Law Report, and in particular Dan's lengthy and incisive first response to Pathway's announcement, and his subsequent analysis of the FDA crackdown.

I have a few overall points to make here.

The end of direct-to-consumer disease genomics?

Nothing is certain yet, but it's entirely possible that these events mark the beginning of the end of DTC genetic testing for health-relevant traits.

The DTC personal genomics industry has so far enjoyed a bizarrely prolonged period of respite from the stifling regulatory embrace of the FDA and other regulatory bodies (while the technical validity of all of the major personal genomics companies is governed by the Clinical Laboratory Improvement Amendments of 1988, there's currently no regulation regarding the interpretation of the raw data).

It has always seemed inevitable that this period would end with a regulatory crackdown, although the precise nature of the eventual regulation - and the events that would trigger the regulatory hammer to come down - were impossible to foresee. Now the hammer is dropping, and although its aim seems capricious (see below), there's little doubt that its long-term impact will be massive. It's certainly not beyond the realms of possibility that companies will be forced to entirely discontinue DTC provision of information for any health-relevant trait.

Personal genomics companies are to some extent prepared for this eventuality. For instance, several of the major companies (e.g. Pathway and 23andMe) have split their disease risk predictions into a separate product from their more "recreational" offerings (such as ancestry, genealogy and non-disease traits), potentially allowing them to maintain a DTC revenue stream even if the DTC disease genomics angle was blocked. (Kudos to Dan Vorhaus for spotting the motives for this behaviour back in July last year.)

Today, GenomeWeb reports that at least one DTC company has gone even further and dropped its direct-to-consumer offering entirely. Navigenics could probably also drop its DTC offering without much harm to its sales, since the company has by all accounts been spectacularly unsuccessful in tapping the DTC market. We may well see the same approach taken by other personal genomics companies in an attempt to stave off the regulatory claws of the FDA.

This outcome would be an absolute tragedy for those of us interested in thoroughly exploring our own genomes. Anyone who has ever tried to get the raw data from their own medical tests from doctors will know how ludicrously difficult this is, due to a combination of bureaucratic incompetence and litigation-shy clinicians. Now imagine that difficulty, multiplied by the sheer scale of genome-level data and the near-complete ignorance of the vast majority of doctors about genetic information.

Comedic blunders from the FDA

While confusion reigns in the DTC genetic testing industry, this whole episode has revealed one thing very clearly indeed: absolute incompetence on the part of the FDA. One cannot help but shudder at the fact that such a transparently clueless agency wields so much power over so many industries.

In a great article over at GenomeWeb, Kirell Lakhman points to a series of contradictions in public statements made by the FDA over the last week (in what he refers to as a "seemingly uncoordinated and contradictory investigation").

Here is an agency that has sat back and watched the industry (albeit lazily, given that it was apparently unaware of Pathway's existence until the Walgreens announcement) for two years, giving no clear guidance regarding its regulatory intentions, and then suddenly announces that retail genetic testing is probably illegal via a quote in the Washington Post.

In addition, the motive for stomping specifically on Pathway seems entirely arbitrary. Gutierrez said in an interview with Pharmacogenomics Reporter (subscription only) that "The fact is that Pathway's bold move to make themselves noticed achieved its end and brought them to our attention", suggesting that the agency would have been happy to let DTC companies continue to operate if they'd done so more quietly.

It's a doubly bizarre statement given that the industry in general (and 23andMe in particular) has been conducting aggressive marketing campaigns to the wider public for a long time. Why did the Walgreen's campaign overstep the mark any further than, say, 23andMe's appearance on Oprah or its zeppelin campaign? It's impossible to know, especially in the complete absence of any substantive guidance from the FDA on what is or isn't acceptable behaviour.

Of course the power of the FDA is so massive, and so arbitrarily wielded (the technical term is "enforcement discretion"), that you won't be hearing many public complaints from personal genomics companies out of fear of retaliation. Instead, the industry is lining up to vow full compliance with the investigations from the FDA and Congress, like shop-keepers telling everyone who will listen how great a job the local gangsters are doing even while they fork out their protection money.

Do we need FDA regulation?

Regular readers will know that I think - for all its faults - the personal genomics industry provides a net benefit to society. Sure, the information provided by personal genomics tests currently has limited utility in terms of health prediction, at least for most of us; but by allowing people to engage with their own data, and generally doing a pretty good job of conveying the complexity and uncertainty of modern genetics, personal genomics companies are non-trivially increasing genetic awareness and literacy, an important public service as we enter the genomic era.

It's worth emphasising that the major personal genomics companies have done a fairly respectable job of self-regulation so far: 23andMe et al. generally present genetic risk information in a way that is far more accurate and accessible than anything we have seen (or are likely to see in the near future) from the medical profession.

It's also important to note that precisely zero evidence exists for the notion that genetic test results are likely to cause serious harm to consumers. So while Arthur Caplan may fret over the idea that customers assigned a low risk of heart disease might "go off and drink milkshakes all day", the existing sociological evidence suggests that genetic risk data alone has relatively little negative effect on consumer behaviour or mental health.

There certainly is room for regulation that filters out the bottom-feeders in the industry - but that is not necessarily a job best done by the FDA. As Dan Vorhaus points out, the Federal Trade Commission, as an agency focused on consumer protection, might be well-placed to step in. In addition, the recently-announced NIH genetic test registry - particularly if it is made mandatory - will hopefully serve as a valuable resource for consumers, allowing them to make informed decisions without requiring them to have an ill-informed clinician hold their hand while they do it.

By all means prosecute companies that make false claims of fact or provide poor-quality assays. By all means provide consumers with additional resources to allow them to make informed decisions. But don't create regulation that makes it hard for new companies to enter the space or introduce new technologies; and if people decide that they don't need their doctor to peer into their own DNA, let them make that choice.

Final thoughts

After years of speculation, the long-awaited crackdown has come. Exactly what type of industry will emerge from the other side is still completely unclear, and we can only hope that regulators restrain themselves from the heavy-handedness they have inflicted on other industries.

Personal genomics is a young field, but it's also a crucible for the future of personalised medicine. Excessive regulation at this stage will cripple innovation in the industry by raising the cost of starting new businesses and developing novel approaches. If the FDA is given free rein to stifle the field with formidable regulatory requirements this will do long-term damage to the development of personalised medicine.

I'd encourage US readers to make their thoughts on this known - write to your politicians, tell them what you've learned from your own genome, and inform them about what a terrible idea excessive regulation would be for the future of medicine.

dgmacarthur Thu, 05/20/2010 - 14:35

Tags

23andMe

commercial genetic testing

counsyl

direct-to-consumer genetic testing

Categories

Hi Daniel,

Thanks for the post. I'd also add that it's not merely an opinion that DTC genetic tests are not likely to cause serious harm to consumers.

In fact, two oft-cited peer-reviewed studies come to mind. One, published in the New England Journal of Medicine last year, had to do with the ApoE gene, which increases one's risk for developing Alzheimer's disease. The study showed that disclosing results of an ApoE genotyping test to adult children of patients with Alzheimer's "did not result in significant short-term psychological risks."
[http://content.nejm.org/cgi/content/short/361/3/245]

The other study, which was led by the National Human Genome Institute, showed that patients who use DTC genetic tests âmay be among the most motivated to take steps toward healthier lifestyles." This paper was published in 2008 in Genetics in Medicine, the journal of the American College of Medical Genetics.
[http://journals.lww.com/geneticsinmedicine/Abstract/publishahead/Charac…]

But somehow I doubt that even these peer-reviewed points will sway the FDA or Henry Waxman.

Kirell Lakhman

Daniel,
All this pity part crap is for the birds.

Personalized Medicine is Medicine Daniel. When you have companies restricting Terms of Service to Not be used for Medicine (in order to avoid responsibility and regulations), how can they be a part of Personalized Medicine?

1. A test for BRCA mutations is medicine, no matter what any terms of service say.

2. Playing medicine without a license is illegal, playing diagnostic lab and selling your wares without CLIA approval is stupid, Which is why Pathway started with CLIA and 23andME and Navigenics ran out to get it PDQ.

3. This is a case of too deep into medicine without any clue how to do medicine.

I had said this for the last 3 years now. Personal Genomics will continue to exist, just not in the fashion which free wheeling sans regulation spit partiers wish to have it.

Is that a bad thing? Is it so bad to say "Slow Down, let's look at what we are doing? Is it the best way to proceed?"

I don't think so. My ex partner and I went down this logic exercise in 2005 and came up with one conclusion

Physicians who know what they are doing NEED to be involved to pick up the pieces and help people understand.

Does a research PhD geneticist need help from a physician? Well, I think the Quake paper indicates, yes a clinician would have helped. At least to get the right studies to evaluate risk.....Not just analyze a genome.

-Steve

Awesome post, Daniel!

Unfortunately, Steve must have missed your point about "the near-complete ignorance of the vast majority of doctors about genetic information"; this is a big bottleneck to the path he is suggesting. In 2010, most American doctors don't even speak about genetics, let alone understand what a DTC genetic test is for or how the results might be interpreted. For that, we'll have to wait for the next generation of trained physicians, starting with the Path residents at Beth Israel Deaconess. Figure a decade before that trickles down to doctors setting up shop in Syracuse, NY. Who wants to wait that long to get their personal genome report?

-Bob

It is my genetic information it should be available to me without interference from the government or anyone else.

If I want I will consult a physician or other expert for help in interpreting and understanding but I should not in any event be denied access to information that is my very essence. To do so is dictatorial.

I have tested with 23andme and I have asked both my primary care physician and three specialists that I see to review my results with me and they have no interest in doing so. So much for professional help in interpreting my data.

Given the bureaucracy of the insurance companies and the reluctance of any physician to release any type of raw data to a patient if these test become medical procedures you will never see you raw data. Modern physicians guard this sort of information â raw data - as jealously as the Catholic church guarded theological matters pre-reformation and for the same reasons â control, period.

I find the increasing amount of control over what I think and do and what information I have access to by the government and professional groups to be alarming.

Andres Bolinaga

I think that the reports of the death of DTC genetic testing industry are greatly exaggerated. The highest regulatory burden the FDA could possibly impose on DTC genetic test kits is to make them Class II medical devices. This would place them in the same category as pregnancy test kits, and such kits are obviously attainable from the local drugstore. Sure, the DTC genetic testing industry might be better off under the current Laboratory-Developed Test (LDT) regulatory regime; however, a Class II designation will hardly decimate the industry.

@Matthew Markus: While I agree that DTC tests would be unlikely to be considered Class III devices, the "highest regulatory burden the FDA could possibly impose" would be to not approve the tests at all, at least in their current form.

Requiring these products to receive FDA approval (Class I or Class III), but to lose the DTC in order to receive that approval, would do considerable harm to the industry. I'm not sure it would decimate DTC genetic testing under the colloquial meaning of that word, but it would certainly do so under the technical meaning. I think that's one of the many points that Daniel makes above.

I agree, however, that developments to date do not necessarily herald the death of DTC. The reality is that we do not yet know what regulatory action the FDA (or Congress) will take, if any. Remember, DTC went through a round of warning letters and fear of over-regulation once before, and removed relatively unscathed.

@Dan Vorhaus: Thank-you for providing a true worst-case scenario. Perhaps I was too bold in my previous statements. My confidence, though, stems from the availability of kits like this:

Home Access Express HIV-1 Test System

I cannot see the FDA getting into the business of judging what information is too frightening or important for a person to know. I firmly believe that the agency is only interested in making sure that DTC genetic test kits face the same scrutiny as other publicly available test kits. Thus, I would be shocked if the FDA acted in a manner that installed physicians as gatekeepers to genetic information.

"This outcome would be an absolute tragedy for those of us interested in thoroughly exploring our own genomes. Anyone who has ever tried to get the raw data from their own medical tests from doctors will know how ludicrously difficult this is..."

About 15 years ago in London I went to my GP. Reception hands me my medical notes on the way to the waiting room. This was a departure, normally medical notes were given straight to the doctor. So I took the opportunity to sneak a look my records, reception sees me, tells me off saying I'm not allowed to look at them...that was the extent of NHS paternalism which should be gone forever.

I hope that the FDA have a well thought out plan for what they are doing and that it's not the case that they were just bounced into an unplanned action by media pressure. They have had long enough. I hope that they will review any evidence of benefits vs. evidence of harm that has occurred over the last few years. Will they listen to customers as well as academics, medics and self-styled authorities on "consumer protection"? It would be great to have personalised medicine for all through medics - if only there were anywhere near enough of them able and willing to provide it.

I hope that they will also look at the consequences of strict control on health information via DTC companies. If it is prohibited (as in Germany) DTC will probably not go away. I don't suppose they will prohibit the non-health related services, I will still be able to get my gene-scan. This could lead to a new generation of "bottom feeders" providing completely unregulated online health interpretation services delivered via servers from any convenient country in the world. DeCode did this for 23andme customers for free, obviously DeCode are not bottom feeders - the point is that it is relatively easy and inexpensive to set up the service, what is difficult and costly is providing a serious service.

At least with the current situation we have a few high profile companies that are under massive scrutiny, keeping them honest and on there toes. None of them are offering magic weight loss or IQ predictions. If a consumer wants to get some relatively bland gene related medical information he/she knows who to go to.

Maybe the current system of "regulation" that has evolved is not too far from the optimum, maybe it just needs a bit of tweaking.

Not all regulation is misregulation. While I agree it would be a shame if heavy-handed interference from the FDA (or Congress) ended the availability of DTC genetic testing, it doesn't seem like that verdict has been written yet. I would think it would be a net win if some sensible regulation on the industry were established so that (a) reasonable providers could cite their bona fides and (b) dodgier companies could be flushed out.

I fully agree with the point that medical professionals are abjectly unprepared to help patients make sense of these data, but that's a whole different problem...

I love how people who are not physicians and some who are not even research geneticists are here to pronounce how horribly not ready physicians are for handling genetic data. While I as a physician who teaches genetics to Yale residents knows that they aren't ready for the intricacies of some things, they know more about genetics than the average Joe who would buy a test at Walgreens or on Amazon.

That is the silliest argument I have heard. What makes Comp Sci 403 know more biology than a physician? It doesn't. What makes anyone at all know more biology, other than PhD level geneticists? Answer most people don't.

Is a bottleneck that destructive a thing right now? No, the money has already been invested in these companies, they won't fold, they will just find another way to sell tests. My guess is a non-medical and a medical version.....Or just straight sequence with no medical interpretation.

Why would you super smart people need that interpretation anyways?

Steve

Steve,

You don't have to be a clinician to know how woefully under-prepared the medical establishment is for genetic information. All you have to do is take your 23andMe or Counsyl profile to your doctor and see how they respond. The vast majority of doctors have no understanding of - and worse, no interest in - genetics.

Let me ask you a question outright: let's say I did get my genome sequenced tomorrow, and had it sitting right there on a portable hard drive. Who would give me the best explanation of its medical relevance: my GP, or 23andMe?

* A 510k app requirement would destroy the industry as currently constituted because it cannot meet the diagnostic standard for GWAS associations. The FDA is a (much) higher bar than Nature or even NEJM.

* It is important to realize the gravity of this situation. A cavity check on DTC genetics companies in public view is not going to be pretty. It will spread to reduce public confidence in ALL genetics. Ultimately this will drive things overseas. Obama on genetics = Bush on
stem cells.

* ASHG is foolishly on the warpath about ancestry too, so I wouldn't count on that as a bolthole.

DTC cos need to use some of those millions and political connections to get this thing halted right away. If they don't fight back with clever political protests they are toast. Get 1000 people to protest in front of Waxman's office snuffing out candles titled "genetic privacy" and "American innovation". Go for the theater and hit back hard. If you admit to wrongdoing it's over, at that point the vultures descend.

This is all happening by the way because of 23's layoffs. Really dumb move. When they were the strong horse they were untouchable. As their aura evaporated they went from invention of the year to an f'ing congressional investigation in 18 months. Sergey needs to brush Anne aside and take the wheel again if there is to be a chance of survival.

@Daniel,

1. "It doesn't take a clinician to know...."
Have you presented your data to your GP? I review these tests all the time. I also teach other doctors how to.

2. "The vast majority of doctors have no understanding of - and worse, no interest in - genetics."
Daniel, should they have an interest? Having an interests assumes there is something important there. In some instances they are absolutely correct in having NO interest in that Genome Scan.

3. " Who would give me the best explanation of its medical relevance: my GP, or 23andMe?"
Well, according to 23andMe's Terms of Service YOU CANNOT DRAW ANY Medical relevance from their "educational" test

I hope you see what I am getting at here. DTCG is at fault for not treating these tests as medically important in the first place. Are they medicine or not?

If they are not, then why should a doctor care about them?
If they are, then let's remedy this gap of knowledge. Rather than get all pissed, go out and try to teach some physician friends about this. Go lecture at your medical schools rather than sit in the medical school lab.

Just stop with this incessant "it's not fair, Genomic Freedom for all" crap!

Make a good argument as to why this shouldn't be regulated. I have yet to hear one.

To all,
Candles on Waxman's lawn is a show, just like SoHo was a show, just like zeppelin's are a show. The administration and the government sees this sort of thing as a sign that you are hiding something. Just go up to the Hill, state your case and let the chips fall where they may. Anything else looks like PR and political hype. Something which people can now see through.

This is not the end of DTCG, it is merely the beginning of a different type of DTCG, that's all.

If it's medicine, say so.
If it is not, say so.

Wow, some exciting posts. Not sure another opinion is needed here, but Dan, I have to agree with Steven. Yes, the FDA is a bunch of bone heads. Be that as it may, DTC is a failure because the product is frivolous. 23nme has the right approach--"genomics can be fun," because that's all it is at this point, a curiosity. If you think current analysis of a genome yields medically relevant information then you have been drinking too much Kool-Aid. Interesting information, yes. Medically actionable, no.

Just finishing re-certifying in Hematology, where our knowledge of genetics, in my humble opinion, is light years ahead of other fields. For example with germline risk of blood clots--we know so damn much about the genes and the biology, much better knowledge base than ALL other diseases...and yet the bottom line is that genetic testing in the absence of other medical risk factors is a waste of time. The studies just don't support doing it in healthy people.

Look, free advice!

Step One: find some actionable knowledge in the genome (not there yet!).
Step Two: "market" tests to MDs. BTW, investors, is there ANY medical diagnostic that makes money? Hm.
Step Three: consider going back to DTC.

Prediction: we will know when we are ready to move from Step One to Step Two when an MD gets sued by a patient with a bad outcome that may have been averted by having a genomic test. If genomic tests are so great, why hasn't that happened yet?

Michael T.
Thanks great points. I really truly agree. However, the likelihood of a lawsuit coming is probably from 2C19 and pharmacogenomics. I think that it will not be malpractice pre se, but may actually be a philosophy of law called Loss of Chance. By not ordering 2c19, in your case 2D6, did that patient with Recurrence/MI get robbed of a chance for a better outcome because you did not order that test.

This is a new philosophy, now upheld in 3 states

That lawsuit is coming, just wait.

-Steve

How exactly are these tests medicinal? They seem to involve no medical practice whatsoever. They do not provide medical care of any kind and they do not in any way manipulate the human body - for better or worse.

Are they not several elaborate statistical analyses broken down into probabilities? It is hardly different from a professional software analyst examining some code and informing another where the potential weaknesses are and what problems are more likely to develop.

The GTC companies should split their operations into 2 - simply providing consumers with raw data from their genome and selling them a software/statistical analysis of such. How that could be construed as medicinal, I'm not certain. The government-knows-bests will have to inform me how the FDA will provide any betterment as they nose themselves into this new arena.

@ Steve Murphy
Regarding your comment "I love how people who are not physicians and some who are not even research geneticists are here to pronounce how horribly not ready physicians are for handling genetic data." ...... I take a lot of offense to this. It isn't just the terrible "PhD geneticists" that you seem to pounce on, but an entire conglomerate of researchers; epidemiologists, statisticians, bioinformaticians, and yes, even clinicians have been involved in a lot of this genome research. It isn't as black and white as saying geneticists vs. clinicians. I believe it truly takes a multi-disciplinary team to understand what all this research means, how it applies to individuals and populations. AND, there has been vast amounts of research done showing that physicians aren't ready for this. Do they know more than the "average joe"? Sure. But does that amount to anything meaningful they can communicate to their patients? Right now, not necessarily. Good for you for getting involved in solving this problem (seriously, I think more needs to be done in this arena), I don't think Daniel MacArthur or anyone else would argue against this (sorry to be speaking for others). But the truth is right now, that 23 and Me could do a better job of interpreting the results!
Regarding whether it should be regulated? Loaded question, but I'll simply answer "Probably, on some level" ... if for no other reason than to get everyone to stop, think about what the test means, realize the meaning of the tests will evolve, and introduce the broader public to this discussion of what needs to be done to prepare for a (potential) era of genomic medicine and personalized medicine.

@Zack,
When the statistical analysis and probability estimate is about whether you will vote republican or not it IS statistics. When it is about whether you will develop debilitating disease, that's called medicine. Pretty simple.

How does that statistical analysis cross the line into medicinal practice? I don't see how that is so simple at all.

It provides no diagnosis or treatment. It's a risk factor, no different than generating a statistical analysis to determine how much more likely you are to die before 50 if you ride a motorcycle sans a helmet. An observation, analysis of data, then turned into a probability regarding your future life. Or is that medicine too?

To re-iterate what others have said in this invigorating post, I cannot see how you do not define DTC genomics as medicine. Let me back up a bit, if you submitted your DNA to a DTC company and then received ONLY your SNP list, solely a list of which polymorphisms you have compared to the reference genome, then I am OK with that. However, the second you turn around and begin to interpret these results and tell people what they are predisposed to or even worse which mutations and subsequent diseases they have, you are practicing medicine.

There is no doubt in my mind (and there shouldn't be any in yours) that some sort of oversight needs to happen in this case. You wouldn't let me running about town with a scalpel cutting people open and you certainly shouldn't be giving people medical information without the proper training or oversight. This usually comes in the form of the FDA or some alternative regulatory body. There is a simple way to avoid all of this nonsense and this is to follow my previous advice, test consumer's DNA and provide a SNP list only. Leave it to them to take this information to a doctor/qualified professional or look it up in dbSNP and see what they find. This is your right as a person and you are assuming all risks upon yourself. Alternatively, if you go to some form of licensed professional you can be sure that you are protected as a consumer and as a PATIENT.

Everyone is entitled to know the secrets of their own genome. It is part of what makes you fundamentally you and most people with any curiosity at all would likely want to see what they're made of. I know I would. Fortunately for me, my life's work is in science and genomics so I understand the benefits and more importantly the limitations of my genomic composition. 99% of the world does not. Let's concentrate on the education and interpretation of large-scale associative SNP analysis before we go ahead and throw the populous in the deep-end. We just took off our floaties after all.

@Zach

If you are told that you have a mutation in, lets say for example the GAA gene, and your mutation was one known to be the cause of adult-onset Pompe's disease; how have you not just been diagnosed? You've felt fine your whole life but now you've been told that you will have a debilitating disease as you age which will severely limit your functions, perhaps even leading to death.

Please explain to me how this is not medicine and how this does not beg for some sort of oversight over the agent administering this test? Even if just to the point of ensuring that all individuals handling your samples have been properly trained and documented as such. I am well aware of the ridiculousness of FDA regulations and I abhor all of the paperwork and endless documentation, but it all does really serve a purpose.

I want these tests to be readily available to all so that we can truly usher in the age of personalized medicine. That being said, what is so wrong with ensuring that we do it right? I'm a free market kind of guy, but I do not have 100% trust in the self-regulation of that free market. Do you?

I don't see how the presentation of that data (gene mutation) is anywhere equal to medical practice. How is it any different that providing the raw data and letting someone look it up on a 23andme.com database? It's just data. I trust the market to handle this one, that's for sure. These companies jumping through hoops will only drive up the costs for consumers and have a prohibitive effect on innovation in the industry.

@Zack

Let's try a real example. 23andSerge says "You have a founder mutation in BRCA1"

That is a medical diagnosis. You have just been diagnosed with a disease.

When they give you the full sequence data of the entire genome, that is not a diagnosis. When you compare it to a database and YOU find out that you have this mutation, you just diagnosed yourself.

A diagnosis of BRCA1 carrier without proper counseling and guidance is medical malpractice. You could sue a doctor for just giving you the information without guidance. Why in the hell would you expect any less from the DTCG company.

Which is "why" companies like Navigenics AND Pathway have physician and genetic counselors.

How can you not understand that the specific gene sequence is a medical diagnosis? I understand, if you look at DNA like computer code and say, "it is just code"

Well, when you say this code is for a disease it is no longer just a code.

BRCA1 mutation IS a disease. That is a diagnosis of a disease. Diagnosing disease is medicine.

It just so happens that the gold standard for BRCA carrier diagnosis IS the genetic sequence.

Vitamins don't diagnose disease, 23andMe does diagnose disease. That is the difference here.

Understand?

For those who don't know. BRCA mutations confers a risk of lifetime breast cancer of 85% and Ovarian Cancer up to 40% The treatment for this disease state is removal of ovaries by age 40, Medication and removal of breasts or increased Mammography and MRI.

So, I ask. How in the ever living bejesus is that not a disease and how is telling you that you have this mutation NOT medicine?

So if I get my own genome sequenced, hop online, and see what risk factors I have via a free database, that's cool. But if someone else looks at that same public information for me, that's a diagnosis?

It isn't diagnosing a disease because it is giving you a probability of developing a disease in the future. Telling a woman she has the BRCA1 mutation doesn't tell her that she does or does not currently have any disease. If it did, it would be a diagnosis. It doesn't - it's an enhanced probability of development.

PS: Your 2nd post on the issue did a wonderful job to disprove your own point as you highlighted the fact that it was enhanced risk rather than an actual diagnosis if disease. You could have picked a much better example, but I'm in no position to form your arguments for you.

Zack,
"Telling a woman she has the BRCA1 mutation doesn't tell her that she does or does not currently have any disease."

You have done it, I have now officially lost my cool.
People with mutations in BRCA1 have a GENETIC DEFECT in DNA repair that in and of itself is a disease.

Which also predisposes to other disease, namely cancers. Just like diabetes predisposes to heart attack.

It is obvious you do not understand human pathophysiology, thus your commentary is disqualified from any further debate on this topic as you clearly do not know what a disease is or is not.

Next time, look things up before you pop off saying what is and what is not a disease.

Just look up the ICD9 code for genetic predisposition to cancer. It is a disease code! DNA repair defect will be a code in ICD10.

Thus, I will not debate someone about the legalities of someone diagnosing another person with a disease as opposed to discovering your own disease status ON YOUR OWN!

I will not play stupid semantic games with someone who has no clue about medicine, genetic disease or mutations. Your lack of knowledge in this space is precisely why the FDA is investigating these companies.

Sorry to be so harsh, but this is the same CompSci 403 argument I hear all the time from people who have no biology or health literacy.

They don't get it, and that's why they can't understand why the FDA and Congress are investigating DTCG.

@ Zach

My example of a GAA (acid maltase) mutation at a specific locus is the diagnosis of the disease. You do not produce a functional enzyme and in this specific example (adult-onset Pompe's disease) you may feel fine now but you have just been diagnosed with a disease. You will certainly show symptoms of the disease later (if not already).

Some SNPs are associated with a risk for a certain ailment. You may get sick, you may not. Some SNPs cause a disease 100% of the time. No associations or probabilities. You got the SNP, you got a problem.

Therefore, with all due respect, please again explain how the discovery of a known mutation which shows 100% penetrance of a disease is not a diagnosis?

Jason, your example was a much more fitting of a diagnosis than Steven's, which is what I wished to point out. A risk factor for cancer is not the same as "you will develop this later in life, guaranteed." This is why his example was flawed compared to yours, despite what he may wish to call a "semantic game".

Steven, what is a disease symptom of the BRCA1 gene? Is there always one? Is it then a diagnosis or a probability? Do all of us not share SNP variation that may or may not manifest itself as a diseased state later in life?

Cases of 100% penetrance are the only logical (in my view) way to argue for a disease diagnosis based on genetic data. Would providing people with the raw data and letting them do it themselves, or with the help of additional software to comb freely available databases, free us from the necessity of FDA involvement? Because basically the argument there is that if someone else looks at the data and comes to a "diagnosis" (which is rather certain, as long as the sequencing is correct), the FDA need be involved. BUT, if I take the data they provide and combs the databases and do a "self-diagnosis", the FDA need not be involved? Seems like an odd, illogical conclusion.

In any respect, I thank those that take the time to discuss this in a civil manner without attempting to demean me. Even you, Steven Murphy, MD.

Using some of the arguments made here against DTC genomics

"A diagnosis of BRCA1 carrier without proper counseling and guidance is medical malpractice. You could sue a doctor for just giving you the information without guidance. Why in the hell would you expect any less from the DTCG company."

Sounds like I should sue my prospective life insurance company for giving me a surprise diagnosis of HepC, with the only counseling and guidance being "we've decided not to accept your application for life insurance". I would image there are other examples of exceptions to your argument. At least Pathway and 23andMe customers know what they may find out, and have made their own choice to find this out about themselves.

Will, I agree, personal choice and the seeking out of such data is important here - nobody is forcing this upon anyone - and Steven also states "Which is "why" companies like Navigenics AND Pathway have physician and genetic counselors" - looks to me like common sense, market forces, whatever you would like to call it, has taken care of this issue (to an extent) already. They certainly do a better job than the insurance company in your example.

@Zack
Only 100% penetrance is a disease? Seriously?
Glad you aren't my doctor or Genome provider.

Murphy, you shouldn't be so enthusiastic about getting the government involved and putting a microscope on things. Would your resume and practice survive a Congressional Hearing? (Rhetorical) Do you think this is good for Genetics, capital G? (Again, rhetorical)

Also, look, there are lots of things we do that are medically relevant measurements that are not medicine.

1) Getting on a scale at the gym. Your weight is relevant to medicine. But you don't need a doctor to weigh yourself.

2) Looking in the mirror. Your appearance is relevant to a whole host of medical diagnoses (e.g. yellowish cast for jaundice, or localized rash, etc.). But a doctor need not authorize you to look in the mirror.

3) Taking various nutrients and supplements to avoid a cold. Your diet is relevant to medicine. But a doctor need not authorize you to take some anti-cold medicine.

4) I don't need a doctor to look at WebMD or get on Pubmed if I have some bizarre condition. I care a hell of a lot more about my health than any MD will, if only because they have 1000 patients and I only have 1.

Etcetera, etcetera.

The solution to improved health is to decentralize and teach people more about taking care of themselves. The fact that GWAS associations have sucky signal strength is not a good reason for banning that movement.

I thank Allah that I work in the completely deregulated computer industry.

What if people stopped us from getting personal computers in the 1970s, assuring us that only experts in numerical analysis could do anything with it, and if we tried to design something on our own we might end up hurting someone since we weren't experts.

What if War Games in the 80s led to people banning individual access to computers on the network because of "hackers" and "national security".

What if the existence of buggy and crashy software meant that all software by everyone had to have premarket approval and go through ISO certification bullshit.

Imagine how much would be lost.

That is what is going to be lost.

Steven - Thanks for answering my questions.

Zack,
I don't mean to demean you. It is just a lot tougher to communicate concepts to someone who doesn't have the same training. Imagine a computer engineer trying to teach me intricacies of COBOL, etc over a few lines of blog comments. I just doesn't work.

I do wish you the best

If my 6 year old cousin was to get her genome sequenced and she had a mutation that could lead to cancer later in life, does she currently have a disease? First, nothing is wrong with her now, she has no symptoms of a diseased state. Secondly, it is not guaranteed she will ever develop the diseased state. I don't believe that's a semantic argument.

It is Semantic Zack
1. You state predisposition to a disease is not a disease state, when the biological defect to predispose is in fact a not normal physiologic (disease) state
2. It is a hypothetical and not true scenario
3. BRCA mutation state is defined as a Disease already

they were caught playing medicine. What about PGx testing Zack? Is that not medicine either?

Isn't PGx testing done in combination with prescribing medication? Of course that's medicine. The entire purpose of the testing is medical.

I really still don't understand this medicine vs. not medicine stuff. Steve seems to be saying that if it's defined as medicine then a medical doctor needs to be involved. But medical advice is given all the time by non-medics (from nurses to pharmacists). With DTC it's not "is it medicine?" but "is it a medical service of such a nature that it needs some regulating?". Probably yes, we do need some sort of regulation. The other question is "is there any level of advice that should be delivered only via a medical professional"? I can't see any use in taking extreme positions and remaining poles apart.

As Daniel says the FDA have had years to be working on this...I hope they have (been working) but unfortunately I bet they havn't, it's not the first time that they have been bounced into doing something about DTC, and I suppose they will fail again)

Would I need a doctor to discuss my family's medical history with my own family? Would that be considered medicine? The actionable information I may receive from a review of my own family's medical history would likely be more informative than a list of my own genetic variants (assuming we're not talking about known disease causing mutations), even if that list came with risk statistics.

Day trip to Tijuana, Piedras Negras, Vancoo, Niagara Falls or Nassau. Get it done there for 200 bucks.

No big.

Nice try, AMA. No banana.

"Make a good argument as to why this shouldn't be regulated."

Isn't this completely backwards? The burden of proof should be on the proponents of regulation to prove why the regulation is required. Given that no one is forcing genetic tests on anyone that doesn't want them, and that the companies involved provide appropriate disclaimers on the limits of their tests, this is one more of the many things that the government should just keep its nose out of. An individual's genetic data does not belong to the government, nor does anyone acquire a proprietary interest in it by virtue of an "MD" at the end of his or her name.

Isn't this completely backwards?

Why yes, yes it is.

And given the complete absence of evidence that receiving genetic risk predictions actually causes harm, the onus is very firmly on the regulation proponents to justify their point of view.

I think regulation is OK - it's the extent of regulation that could be the problem and the wisdom of any regulations that will be applied under the current conditions (controversy, knee-jerk, pressure from ignorants above, and a very fast moving field). Any restrictive control should, as said here, require strong justification with clear evidence of actual or potential harm and also be equally clear that shutting down DTC (if that were to happen) would not actually be harmful itself. I'm certain though that it would be harmful, for many reasons, most are in Daniel's post.

Excessive regulation would be terrible - something along the lines of the HGC proposed Code of Practice would be ideal and it embraces most of the points from Dan Vorhaus at Genome Law Report

@ SteveMD
I agree that this can be qualified as practicing medicine.
So what?
Why are MD's the gatekeepers of my personal biological information. They are the only one's allowed to give me information about my body?
I do not have an MD, but this is my body. I should have the right to ask and pay for any darn test I want on my own body without my MD's permission. If I want to know my D3 levels, why should I not be able to get that info without the consent of my MD? It is so frustrating.
Interpretation of the results is a different matter entirely. But simply getting the testing should be a free individual choice not restricted by government or MD's. It is none of your's or the government's business if I want to get my own genetic test. I don't need you to protect me from myself.

@ Ariel

I don't need you to protect me from myself.

Ahh, but apparently you do as the consumption of illegal drugs or of alcohol under the age of 21 are forbidden. Big Brother will send you to jail if you do not do what is good for you. Let's face facts here, the government of the U.S has taken an active interest in determining what is good for you and what isn't. This is the way it has been and is the way it will be. Regardless of how you feel about it this is an undeniable truth.

@Daniel

And given the complete absence of evidence that receiving genetic risk predictions actually causes harm...

As I am sure you are aware, genetic testing is not just the determination of genetic risks that can be cured with the panacea of a disclaimer. Some of the information that you will receive has the potential to be more than just the predisposition to disease or reaction to a pharmaceutical. You may actually be diagnosed with a disease if you so happen to find a particularly nasty SNP in your genome. This has enormous consequences to those who may be doing a genetic test for fun but then find out some truly sobering news. This is not to say that a doctor has to administer and explain the results of your-favorite DTC test but there certainly needs to be some form of oversight beyond submitting information to a website. These companies (or any other) need to have some form of accountability for what amounts to potentially delivering a clinical diagnosis.

@Jason
I don't believe getting information about your body is illegal - and the act of testing poses no risk.
To extend the point, I could really care less about current state of politics and invasion of government. It ebbs and flows. I am pretty sure our constitution stands, and article I section VIII providing limits on functions of government has not yet been repealed. So until then, you and the government can leave me alone to buy whatever the heck test I care to buy that is available to me. Why do you or the government care? Why should it be any of your business?
Also, god-forbid someone gets diagnosed with a disease by someone other than their doctor! The whole world is going to go down the toilet!!! Thank goodness a test like this is available, and thank goodness people can get a diagnosis early that hadn't otherwise been caught by their too-busy to take the time to actually run some diagnostics doctors.
I am only 31, but I like to know my baselines. I don't believe anything is wrong with me, but I love information. I want my D3 levels, I want my cholsterol, and i would love to have even more info but despite being a more-than-willing private pay client my doc isn't interested in ordering any of these labs. If I want to get any of this info, I have to go to the Cleveland Clinic Wellness Program and pay tens of thousands.
So shame on any of you doctors who think patients shouldn't have the right to get information about their body on their own. We are capable people, not ignorant morons who can't handle information about their own bodies. It is so insensitive and insulting the attitude MD's have towards us "patients" We are actual people with actual brains who can actually handle somethings without you giving us permission.

@Ariel

I want my D3 levels, I want my cholsterol, and i would love to have even more info

And wouldn't you want to be sure that the people who manufacture and distribute your test results are upheld to the highest quality standards and practices? Or do you also want to do your tests yourself in your garage.

Nobody here is arguing against these tests, certainly not me. This is about oversight, of which there is currently none very little. I am not a physician nor do I play one on TV, but your attitude towards your health is a little confusing. So you are upset that your doctor will not order needless tests for you to know your own "baseline". However, you are also upset that you can actually get these tests but they cost you a lot of money? Children want what they want when they want it.

If you truly desire to know any of your biological information which is not directly related to a health concern, then why are you upset that a doctor will not waste hospital/laboratory time on your curiosity? I would imagine that most laboratories are maxed-out dealing with patients who have genuine medical needs as opposed to your self-tinkering. If you want the tests then pay for them. Don't complain to me about the price of the tests, this is set by the market. If you want to have your genome sequenced, go right ahead and do it. But if you are going to try to extract medically-relevant information from your SNP list (which you most certainly are) then it needs to be regulated in some form. Just because the DTC-companies say it is not medical information does not make it so.

Here is a shiny red button. DO NOT PRESS THE RED BUTTON. You are entranced by the beautiful radiance and succulent aroma of the shiny red button. You are seduced by the subtle sophistication of the glowing omnipotence and benevolent charms of the red, candy-like button.... but for God's sake man, DO NOT PRESS THE RED BUTTON.

I am perfectly willing to pay for any and all tests, and my argument is that they should be more widely available - not more regulated and expensive. I support moderate regulation to a very limited extent. I am referring to a more general anger towards MD's and their authoritarian possessiveness of their power. It is bad enough I have to get an MD's permission to get my D3 tested.
I read things everyday, advice from Dr.'s like Dr. Oz, research studies, Dr. Roizen from the executive program in which I am involved, Sirius Doctor radio - they recommend you test for this, test for that, ask your doc about this, get your skin checked, etc.. When you actually follow through and do these things, doctors are annoyed that you are wasting their time unless you are suffering from some serious illness. That is not the way medicine should work. I am sick of having to go through an MD for every single little thing. There are such simple, harmless, basic things informed patients should have the right to do without bowing down to the almighty MD.
Because my doc doesn't have time, and is annoyed by any patient that isn't sick, and perhaps threatended by any patient who comes in with information, then I have had to join the executive health program. Very few people can afford this. So are you telling me that the average Joe shouldn't be bothering their docs with requests to keep up with preventative health and wellness? They don't deserve to know their levels here and there to make sure they are on top of things? It should only be for the elite? Regular MD's don't have the time and don't care? There is such a paradox between the public message to patients and the reality of what happens when you see your doc. I am sick of doctors thinking they are the only one's who know what is right for patients. We have the ability to research, understand, and think for ourselves. And if I see my doc for my physical and request a few tests, paying out of pocket, why the heck does it matter to her whether or not I get them even if she doesn't think I need them. Is the hospital trying to make money or not? I don't want to hear excuses about the lab being too busy with sick people that is offensive and ridiculous. I don't deserve preventative medicine? I am not sick enough? Unbelievable.

I do personal genomics in the East. We sell directly to the customers but we have MDs to interpret the results for them. So far no government agency is bothering us much yet.

I may be a bit biased. But I am with Ariel here. It is quite difficult to get docs to let us do tests on ourselves to satisfy our curiosity. I found quite many latent Celiac Disease patients (the double DQ2.5 carriers). And my work help them get diagnosed with CD and can take care of themselves better.

I agree that there should be regulations but they should only be limited to regulating genotyping/sequencing quality which is already covered by CLIA.

We all know 23andme et al are not doctors nor do they claim to be. If people do get BRCA positive result, I think they will then talk to real doctors for confirmation test and their professional advice.

I don't really understand why MDs here are against these tests, it seems to me they might bring more business to you.

Does anyone have evidence that risks of freedom in genetic testing outweigh the benefits?

Anyone? Anything?

Wow - I'm clearly late to this discussion but I'm going to jump in anyway. Starting from first principles: this is my DNA. A technology exists to help me read it, or at least part of it. Why do I suddenly need to recruit all the medical infrastructure to do this? I hope the medical professionals who want genetic testing kept under the "medicine" tent understand how appalling this argument is. It sounds like sacred knowledge being protected by an elite. Yes, yes, I know it's not that simple, but come on - you have to see the parallel.

Next step: My DTC provider dumps a list of SNPs, with no information or analysis. However, I go to snp-wiki and I find I have the minor allele for SNP rsX, which is 80% associated with dying horribly. Who, exactly, is practicing medicine? The DTC company? The database? Me?

Is it only medicine if there's an ICD code associated? Is it always medicine if there's an ICD code? Who decides what gets an ICD code - and more importantly, does this decision then render all related knowledge off-limits except with the advice and consent of a doctor?

Obviously the case is a strawman. A DTC company could not build a business around a raw data dump. But I can get my blood pressure and cholesterol levels checked with over-the-counter techniques. Does hypertension have an ICD code?

I totally agree with East that these labs should be regulated for quality, but it's my genome, they're my variants, and I've had them all my life. Why can't I read them?

@Traver,

I can understand why people not trained in medicine have a hard time understanding this.

Your blood pressure measurement IS NOT A DIAGNOSIS

Hypertension IS and can only be made after 3 BP measurements in the same setting.

Your ACGTs are not a diagnosis

BRCA1 Mutation carrier IS

No strawman, in fact a very important distinction in regulation AND liability. Which is precisely why we need to address it FIRST prior to applying regulatory frameworks.

-Steve

@Steve,

Thanks for the response. I think I'm beginning to see the root of the problem. It appears that, in the medical world, "diagnosis" carries a much broader meaning than just the condition it describes. "I carry a BRCA1 mutation" means just that, to me, but whoever gives me that info carries a whole load of legal, ethical, and liability baggage.

There's also clearly a gray area between personal health information (e.g. measuring my own BP over time) and formal diagnosis (I have hypertension). I can, with reasonable probability, come to the same conclusion as my doctor regarding whether my blood pressure is in fact elevated. We can acquire the same information. But the formal diagnosis of hypertension, not to mention the formal course of action following it, opens up a whole different world of, as you say, regulation and liability. And, frankly, I can see why a physician would be displeased with even that level of self-diagnosis: Joe Public's false discovery rate must be overwhelming.

In the few cases where genetic tests can predict disease, however, that gray area becomes a very sharp line: I either have snp X or I don't. Provided, of course, the test is accurate - but I think we all agree on regulating that. But the point is that it doesn't matter whether the test is done in the controlled, repeatable environment of a doctor's office or whether I'm spitting in a tube at home. The result is going to be the same.

I just don't think restricting access to that information is a defensible position. In the long run, anyway. I'm obviously betraying my ivory-tower academic roots here.

Have I completely missed the point? Is the distinction I draw between information and diagnosis artificial?

-Traver

I prefer to think whether my service can help people or not. If letting a person know about her BRCA status and it can prompt her to seek doctor's advice and save her life, I am all for it. I don't see any benefits for her by keeping her in the dark. A BRCA positive person without any family history as reference most likely won't take the BRCA test at any MDs' office. If my test can prompt her to do that, I think I do the right thing.

@Traver,
Absolutely brilliant! You've got it! If I give you the diagnosis of hypertension as your doctor, I am obliged to treat that disease and prevent progression as best as I can. If I don't I am liable.

If the DTC company tells you diagnosis, they aren't.

The same is true of genetic diagnoses.

@Geneticist from the East

I agree, but unregulated, how can I trust you are actually testing BRCA1???

WSteve

For tests that have well known diagnostic potential, I don't mind being regulated as well.

I assume Myraid is also regulated in the same way, right?

Goodness. The personal genomics industry wants to be "self-regulated"? Well, every industry on earth would love to be self-regulated, I'm sure. Heck, the oil and banking industries used to complain about "excess regulation" all the time, and we can definitely see just how well-founded their concerns truly were NOW, can't we?

Let's keep it simple here. The raison d'etre of governmental agencies like the FDA and the FTC is to protect consumers. If you have personal genomics companies offering their customers health-related information that their customers can't independently evaluate(not everyone gets to spend a decade in college studying human bio, you know), it's important that these companies be regulated to ensure they aren't ripping their customers off. As a geneticist, you're able to assess the quality of the product 23andMe sells you. Not everyone else is. The regulatory bodies are there to establish standards to protect the public, and that's precisely what one would hope they will do.

And of course I don't think these tests should be available to consumers only via clinicians. But more regulation is necessary and long overdue.

@Steve

I don't think 23andme claimed to test for the whole BRCA. So theirs is not a diagnosis. But you might think otherwise though.

"The raison d'etre of governmental agencies like the FDA and the FTC is to protect consumers"

No. The rationale is to (1) increase their budget and (2) avoid negative press, which are the only checks on their growth.

What incentive does the FDA have to "protect consumers"? If patients die because of lack of access to drugs, the FDA is currently not liable.

Work in the federal government and you will quickly realize that people are human and political there just as they are in business. The key difference is that businesses can go out of business if they don't serve their customers. The introduction of a regulator into a voluntary transaction between an individual and a business changes the dynamic. A regulator is your most important customer because they are the ones with a gun pointed at your head. If they don't like your product they will fine you, destroy your business, and throw you in jail.

This distorts every decision you make going forward. The regulator does not want new innovative stuff, they want stuff "according to spec". The regulator does not like it if you make a lot of money because profit itself makes them envious and suspicious -- they may not have your technical savvy or your gadgets, but they'll have your ass if they want it. They also now have something to trade: if they lay off your business, you give them a plush job as "director of regulatory affairs" the next year.
Thus it is regulators who corrupt business rather than vice versa. Take a third string PhD, give him a title, a govt job, and a gun -- and then empower him to fine and imprison all those innovative guys who surpassed him in college and grad school. "Those who can't do, regulate".

Nothing I say here should be surprising if you think of the police. Everyone knows about police brutality and the fact that police can and will ticket you if they feel like it or if they need to make quota. The FDA is exactly the same way; the main difference is that they treat entrepreneurs like criminals.

"But if you are going to try to extract medically-relevant information from your SNP list (which you most certainly are) then it needs to be regulated in some form."

Why?

My SNP list is mine. If I want to know it, and extract something from it, that is my business.

Why do I need permission from a group of people with a vested financial interest before I can do that?

Does the medical profession really think it has the right to control what I am permitted to know about myself?

In equity, it cannot insist that it must be involved in the process, and then insist that it has the right to control what I am told. If any other profession tried to do that, it would be roundly condemned, and quite rightly so.

@Sandgroper:

In principle I agree with you completely, but we may be talking about different things. If I'm going to extract medically-relevant info from my SNP list, then I absolutely expect that SNP list to be accurate, and that warrants some level of regulation.

@Traver - Yes, I'm sorry. I understand your point, and have some sympathy with it.

But regulation is no panacea. It will not prevent errors. I figure it's up to me to guard myself against possible errors, and Dan has told us some ways we can do that.

What I absolutely do not want is a physician-mediated process. That's what I have now, and I don't want any more of it.

"What I absolutely do not want is a physician-mediated process. That's what I have now, and I don't want any more of it."

I agree, but I also don't want the forbiddance of a physician-mediated process, either.

I'm certainly glad I have used 23andMe to examine some part of my own genome. Of course, the information available (both that is sequenced and, mostly, what we can make sense of now) is only a tiny part of my genetic information but this information is mine. I was born with it and I feel I have a right to it. There's nothing really amazingly fabulous or awful in it, as it happens. It's inherently very interesting to me simply because it is mine. I have a bachelor's degree in biology and with 23andMe's help I think I do quite a good job of making sense of the information.

The end of the deCODEme personal genomics service?

dgmacarthur — Sun, 14 Feb 2010 08:45:00 +0000

The end of the deCODEme personal genomics service?

This piece in Newsweek is a neat summary of the rise and fall of Icelandic genomics giant deCODE Genetics. Regular readers of Genetic Future will be aware that the company has been steadily bleeding capital ever since its launch over a decade ago, and recently declared formal bankruptcy. Since then the company has been bought up by US-based company Saga Investments. (For an excellent analysis of the implications of this sale, see Dan Vorhaus' post on Genomics Law Report.)

A reader emailed me to point out that buried towards the end of the Newsweek article is an ominous paragraph for customers of the company's personal genomics arm, deCODEme. Despite earlier promises that the personal genomics service will be continued, the article gives the strong impression that the days of the service are well and truly numbered:

A few weeks ago, meeting with StefÃ¡nsson in Boston, he proved his point. The two were mulling the fate of deCODEme, the consumer diagnostic test. StefÃ¡nsson said he still hoped to be "very modestly marketing" the test as of next year. Collier raised his eyebrows and said, "If you want one, you'd better buy it now." In other words: forget it.

The loss of deCODEme would mean the end of one of the "Big Three" personal genomics companies out there right now; and there are also increasing signs of financial strains on the other two competitors (23andMe and Navigenics). It looks as though 2010 will be a year of turnover for the industry, as some of the early players are replaced by newcomers offering quite different services and business models (such as the extensive carrier testing offered by the recently launched company Counsyl).

What will happen to the customer data generated by deCODEme if the service is abandoned? No-one knows for sure, but those interested in this question should revisit the excellent posts by Dan Vorhaus and Lawrence Moore on this topic here, here and here.

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dgmacarthur Sun, 02/14/2010 - 03:45

Tags

commercial genetic testing

The data will be sold.

That's my guess.

It looks to me as if plans are afoot to improve the services there. So either this decision was made very recently, or they're making one final push to see what happens over the next few months, and if nothing changes they'll probably close shop.

The end of the (deCODEme) personal genomics service excellent entry is actually a double question (when parentheses are used).

I would refrain from commenting on the "end of deCODEme" as a single company, even if it was the first, and part of the "top three".

Daniel McArthur (and just about everyone) point out that survival of any DTC hinges on a better business model. As such, the other leading two (Navigenics and 23andMe) are no different. Their "growth pains" are substantial, e.g. the inevitable upgrade from microarrays, interrogating the tiny (up to 1.6 M bases out of 6.2 Bn bases) "SNP-tests", towards a targeted (algorithmic) search for structural variants over the affordable full human DNA are contingent only on time/money (to the extent that they are convertible, with limitations). Organizational issues are also very frequent and are eminently solvable.

The key questions are, therefore, if genomic testing service has a future at all - and if yes, what is the business model that will sustain it.

Francis Collins' book, fresh off the shelves, "The Language of Life - DNA and The Revolution in Personalized Medicine" effectively and definitely answers the naysayers. Futurists who may still voice their doubts about the future of genomic testing simply have not done their homework. Most likely did not get a chance yet to read Chapter I., page 1. of the book with the title "The Future Has Already Happened".

In all fairness, those behind the curve are lag only few months, perhaps up to two years. The book appeared early this year, and as we learn on page 84 Francis Collins in 1996 "found the idea of direct-to-consumer genetic testing completely unimaginable in my lifetime". Moreover, his turn-around only happened a mere two years ago (page XVII)- and the final conviction (as usual) was due to his own genomic testing by all three companies last Spring. Proclivities found were in line with his family history (as far as elevated risk for macular degeneration was concerned), but did not apparently occur in his family (as far as diabetes type II is concerned). Dr. Collins, an MD/PhD, head of NIH, immediately went on prevention program for both, modifying his diet, body weight (visible on his before and after portraits), etc; he apparently found DTC results "actionable". Conclusion of his chapter "So Personal Genomics is here..." reads "Given the early stage of DTC genetic testing, there are [those]...arguing that it is premature for this kind of information to be made available for consumers. I am not one of them" (pp. 89)

The "open question" remains, therefore, in what business model can such testing pay for itself in a manner (like the first rudimentary OS; "DOS", followed by "Apple OS" and "Windows" and killer apps) promising a hyper-escalation in a business sense.

One of the answers is given by (full disclosure; my new venture) HolGenTech, see YouTube where the heretofore "open" DTC-loop (not closing on empowerment of consumers) becomes a "closed business model" by both tooling up consumers for personal and participatory prevention programs, as well as providing interoperability of their genomic- and health-date, all overridden by their personal preferences.

pellionisz_at_junkdna.com

If Newsweek is slagging off GWAS, as it does in this article, does that mean GWAS has officially jumped the shark?

Personal genomics is getting serious: Counsyl emerging from stealth mode

dgmacarthur — Fri, 22 Jan 2010 16:00:00 +0000

Personal genomics is getting serious: Counsyl emerging from stealth mode

Disclaimer: my wife and I have both received and used free testing kits from Counsyl.

Counsyl is a rather enigmatic player in the personal genomics field: apart from a brief mention in Steven Pinker's excellent NY Times piece over a year ago and an even briefer post on a Newsweek blog late last year, the company has been in determined stealth mode for much of the last two years.

All that was publicly known about the company when I wrote about them last year was that they will be offering a large-scale carrier screening test: basically, allowing couples who are considering having a baby to test their genomes for a wide range of severe mutations that might - if both potential parents carry copies in the same gene - result in severe disease in their children. Couples who discover these types of variants could then arrange for pre-implantation genetic screening to be performed during the process of IVF.

While other companies (notably 23andMe and Pathway Genomics) do offer limited carrier testing in addition to their more "recreational" tests (things like ancestry and complex trait prediction), Counsyl's offering is intensely focused: the goal is simply to pick up as many known serious disease-associated mutations as possible.

There are two things I find particularly intriguing about the Counsyl approach.

The first is that the company appears to have convinced a number of large US insurance companies to cover the costs of the test, making it effectively free to a non-trivial fraction of potential customers; that will make the test accessible to a pretty broad slice of the public.

The second is that the company will undoubtedly face challenges from various quarters about the ethics of carrier screening. To me all such challenges are irrelevant in the face of the benefits of screening and, as the company's press release emphasises, there will be especially strong benefits of screening for minorities. Nonetheless, it will be interesting to see how this debate plays out over the next year or so.

For the last two years the personal genomics arena has been dominated by the testing of common variants with very small effects; it appears that this is just about to change dramatically.

Here's the press release:

Free with insurance, new pre-pregnancy test saves lives while dramatically cutting health care costs

STANFORD, California -- January 22, 2010 -- Genetic diseases like those seen in the new Harrison Ford movie "Extraordinary Measures" can now be prevented with a simple saliva test which is free with insurance for more than 100 million Americans.

The movie centers on the real-life efforts of the Crowleys, a Connecticut family trying to find a cure for a rare genetic disease affecting two of the family's three children. The condition wasn't detected until after their children were born.

Now, couples can take a Universal Genetic Test before pregnancy to determine whether their baby is at risk for more than 100 life-threatening genetic diseases. At-risk couples may then use a well-understood procedure called IVF/PGD to protect their child from genetic disease and ensure a healthy pregnancy.

This Universal Genetic Test was invented by scientists from Stanford and Harvard and brought to the public via a Stanford startup named Counsyl (counsyl.com). It is now offered by physicians at more than 100 prestigious medical centers across the country, including Yale Fertility Center (see counsyl.com/map), and has attracted the support of doctors from the nation's largest hospitals, prominent academics, religious leaders, and families with genetic disease.

Broad Support Among Prominent Physicians for Universal Genetic Testing

Dr. Pasquale Patrizio, Director of the Yale Fertility Center: "Every adult of reproductive age needs the Counsyl test. It is unusual in that it benefits all three parts of the health care triad: patients, doctors, and insurers. A child stricken by preventable genetic disease often dies in infancy and costs the bereaved parents millions in medical bills. A five minute saliva test that prevents this is a money saver, a time saver, and most importantly a life saver; it really is a no-brainer."

Dr. Thomas Walsh, Director of the Male Fertility Laboratory at the University of Washington: "Genetic testing has been recommended for all adults before pregnancy since 2001, but like many topics related to planning a pregnancy, awareness of this issue continues to lag. This test covers several key genetic diseases, including cystic fibrosis, spinal muscular atrophy, sickle cell, Tay-Sachs, and many others. The results of testing enable couples to make an informed decision before conceiving a child."

Dr. John Marshall, Chair Emeritus of Ob/Gyn at Harbor-UCLA Medical Center: "Because the test can be taken in the privacy of one's home as well as in a clinical setting, it reminds me of the first 'at home pregnancy test'. This 'at home carrier test' is very similar in that the healthy adults who take it generally test negative, with those who test positive referred for medical followup. It thus completely reshapes the debate over so-called 'DTC' testing -- offering this test over the web as well as in a clinical setting is simply a moral imperative, as it is the only way to get needed care to people in rural areas who may be far away from large hospitals."

Dr. Michael Levy, Clinical Professor of Ob/Gyn at Georgetown and Director of IVF at Shady Grove Fertility, the nation's largest IVF center: "Parents who know their carrier status before pregnancy can take preventive measures to have a healthy child. Because new techniques like PGD are used before pregnancy, they avoid the ethical dilemma of termination that was previously a roadblock to wider adoption of carrier testing."

Dr. Steven Ory, Past President of the American Society of Reproductive Medicine: "The vast majority of babies born with genetic disease have no family history. However, there are now tests available to prospective parents that can identify couples at risk of producing an affected child. That's why it's so critically important for all parents to get the Universal Genetic Test before pregnancy. "

The New Standard of Care at the Nation's Largest IVF Centers

Dr. Sherman Silber, Medical Director of the Infertility Center of St. Louis, and author of the best-selling book, "How to Get Pregnant": "Every adult thinking about having a child should get the Universal Genetic Test before pregnancy. The standard of care used to be to test at most one disease, and usually during pregnancy when the options were more limited. Now we can give couples this simple saliva test before pregnancy to cover dozens of diseases. It is a genuine breakthrough and one of the first real fruits of the Human Genome Project."

Dr. Arthur Wisot, Medical Director of the Reproductive Partners Medical Group in Los Angeles: "The Counsyl test is appropriate for everyone trying to conceive because it is the first test that is both practical and economical to screen for so many genetic diseases. Between the Counsyl test and preimplantation genetic diagnosis when positive results are found in both potential parents, couples can now protect their baby from developing any one of over a hundred debilitating and lethal genetic diseases with just a saliva sample. This test is the future of genetic screening."

Dr. Ian Hardy, Medical Director of Fertility Centers of New England: "We have been offering the Counsyl test to our incoming patients as part of their standard evaluation with exceptional results. It is an easy-to-use saliva test which is covered by most insurance plans and allows couples to be screened for major genetic diseases: cystic fibrosis, spinal muscular atrophy, Tay-Sachs, sickle cell anemia, and dozens more."

Dr. Kaylen Silverberg, Medical Director of Texas Fertility: "The Counsyl test replaces a battery of more expensive blood tests. It provides a couple and their physician with much more information for a fraction of the cost. Counsyl testing represents a quantum leap forward in pre-conceptual planning for couples - especially those concerned about having a child with a genetic disease - as it is safe, affordable, and easy to use."

Dr. Michael Soules, Medical Director of Seattle Reproductive Medicine: "Our clinic's new Preconception Program offers expanded genetic testing whereby the couple is screened to check that they aren't each a carrier for a serious disorder that could affect their offspring. The new Counsyl test is the simplest -- using just a saliva sample -- and most cost-effective way to do genetic screening as it checks for over 100 significant disorders with a single sample. Enlightened insurance carriers are paying for this test as it saves them the major future expenses of covering a chronically sick child."

Dr. Mark Perloe, Medical Director of Georgia Reproductive Specialists: "If you are planning to have children, you need to get the Counsyl test. Georgia Reproductive Specialists prides itself on offering our patients the latest advances in medical science, and we are now recommending the Counsyl test to all patients considering pregnancy."

An Advance for Women, Minorities, and Families with Genetic Disease

Professor Henry Louis Gates of Harvard University: "As the first genetic test for all ethnic groups, the Counsyl test represents a genuine breakthrough for minority health. With one test for diverse communities, African Americans and Hispanics can benefit from a new technology that actually reduces health care disparities."

Elena Ashkinadze, Program Supervisor in Genetics at UMDNJ-Robert Wood Johnson Medical School: "Because Counsyl's test simultaneously covers diseases from many ethnic groups at a considerably lower cost than standard blood tests, it promises to make carrier testing affordable for previously underserved patient populations, including African Americans and Hispanics. The current practice is mostly to screen once a woman gets pregnant. With Counsyl's test, we can change the emphasis to pre-pregnancy screening when more options, including preimplantation genetic diagnosis, are available. Ideally, women should understand that having carrier testing before pregnancy is as important as refraining from alcohol during pregnancy."

David Brenner, Director of the Dysautonomia Foundation: "As a parent of a child with a genetic disease, I wouldn't want another child to suffer from what my son has endured. Nothing is more important than safeguarding the health of our children, and this test is such a simple and powerful way to prevent terrible suffering."

Rabbi David Wolpe of the Sinai Temple in Los Angeles: "Several years ago, a mother whose son was born with Tay-Sachs said to me sadly 'The Rabbi made sure to tell us not play Wagner's march at our wedding, but said nothing about being genetically tested.' Ensuring that Jewish couples -- and others -- are genetically tested is a critical task."

Professor Steven Pinker of Harvard University: "Universal genetic testing can drastically reduce the incidence of genetic diseases, and may very well eliminate many of them." Last year, Professor Pinker and his wife, the novelist Rebecca Goldstein, took the test and learned that they were both carriers for familial dysautonomia. Their children would have been at risk for this life-threatening genetic disease -- underscoring that the value of genetic testing is far from hypothetical.

About Counsyl

The Universal Genetic Test was developed by Counsyl, a Stanford startup founded by social entrepreneurs and philanthropists. Counsyl's mission is to end the needless suffering of preventable genetic disease.

To ensure that every ounce of prevention enables a pound of cure, each test taken helps Counsyl fund treatments for children living with genetic disease. More than $50,000 has already been donated to nonprofits over the course of 2009. For the next month, donations will go to the John F. and Aileen A. Crowley Foundation in honor of John Crowley, the Notre Dame and Harvard Business School graduate whose life is the basis for 'Extraordinary Measures'.

Press Contact

Balaji K. Srinivasan

Counsyl

bk@counsyl.com

(650) 733-GENE

NOTE TO EDITORS: For additional information please visit Counsyl's website at www.counsyl.com. A list of selected clinics is available at counsyl.com/map.

'Extraordinary Measures' is a trademark of CBS Films. Other company, product, and foundation names may be trademarks of their respective owners.