DTC Genomics Update

I have fallen a bit behind in posts about the DTC genomics field.  One change in my posts to note with respect to this subject, I am going to start using the term “personal genomics” to describe the field, since it seems to better capture what these companies are about.  Here are some developments from the last few weeks:

23andMe patent for Parkinson’s

23andMe received their first patent titled “Polymorphisms associated with Parkinson’s Disease” in May.  As discussed here  and here this news reveals a bit more about the company’s commercial aspirations and creates a rub with their espoused culture of “democratization of genetic information”.

Navigenics bought by Life Technologies

On July 16 Life Technologies announced that it had bought personal genomics provider, Navigenics for an undisclosed amount of money.  It appears that LTI purchased Navigenics for its CLIA lab and to gain an entrée to genetic testing.  No word from LTI on pursuing DTC genomics.  What does this say?  Near term, even Navigenics thought personal genomics is going to be slow moving and an uncertain success.

23andMe seeks FDA approval

In July, 23andMe announced that it would seek approval for seven of its tests from the US Food and Drug Administration.  The nature of the tests was not specified.  As you will recall, in 2010 the FDA tangled with DTC genomics/personal genomics companies over the accuracy of their tests and related medical information.  This looks like another hint at the strategies 23andMe will use to actually make money in the personal genomics business.

Where does the industry stand now?  It is a struggling field, fraught with challenges, including relevance, uncertain social acceptance, and potentially a new level of government regulation.  Is it a field on the brink of extinction or explosion?

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DTC Genomics Profitable?

Maybe there is hope that 23andMe, as well as the other DTC genomics companies can make a living in the end:

http://www.bio-itworld.com/els/2012/05/29/23andme-announces-first-patent.html

Although, it is not clear how useful this particular patent will be.  More detailed discussion here:

http://www.genomicslawreport.com/index.php/2012/06/01/patenting-and-personal-genomics-23andme-receives-its-first-patent-and-plenty-of-questions/

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Lessons learned from tumor heterogeneity

My recent blog post, Tumor heterogeneity, revealed…, discussed the New England Journal of Medicine article by Gerlinger and colleagues describing the genetic heterogeneity found both within a patient’s individual tumor nodules and between spatially separate nodules.  There has been a substantial amount of discussion of this work and angst about how it might signal the end of personalized medicine even before it really got started.  I don’t believe that will be the case at all.  To the contrary, this paper made interesting contributions in three conceptual areas that may help pull the field forward.  These areas are the 1) relevance of prognostic gene expression profiles, 2) the nature of “driver” genetic mutations, and 3) the pathogenesis of cancer itself.  All of these areas are, in my opinion, very important to make headway in before personalized cancer medicine can become a truly effective tool in medicine.

Heterogeneity in gene expression profiles across the tumor specimen

The result that most seized on to proclaim the demise of personalized medicine was the finding that gene expression signature from spatially separated parts of a tumor nodule yielded different assessments of prognosis.  The implication is that a single biopsy specimen is inadequate to generate an accurate prediction of clinical course or response to treatment.  Most likely that is at least partially true.  However, the issue is with sampling, rather than the molecular biology.  We have known for decades that tumors have variable histology within their mass, with some regions reflecting poorer prognosis than others via their histologic grade.  Rather than reflecting a conceptual disconnect that dooms a new paradigm, it looks more like a technical problem to solve, which should be no surprise along this new path.

Convergent evolution

Both the Gerlinger paper, as well as others (e.g. Walter et al, NEJM), using NGS have now demonstrated that within a single patient the same gene can be found to be mutated multiple independent times, suggesting that this mutation creates a change in gene function that participates in the development of the cancer.  This had not been shown in humans before.  This finding will be useful for clinical diagnostics  and it may be game changing in basic research.  In clinical diagnostics identification of a multiply-mutated gene would give additional confidence that the damage it represents is causal and may help select targeted therapy.  In basic research, identification of such genes would represent novel evidence of the causality of specific genetic changes in the disease process.  This type of evidence is a smoking gun, a sign post saying “Needs to be mutated to reach this disease state”.  This type of evidence, which only deep sequencing can yield, is a new and useful application of NGS that was not previously available.

Pathogenesis

The picture that the Gerlinger paper, Walters paper, and others paints is one of clonal evolution of cancer.  This type of work paints this picture with clarity that has not been achievable before.  What is striking to me is that these results make it harder to ignore the concept that these molecular alterations, as important as they clearly are in the progression of cancer, may not be the cause of cancer.  They beg the question, “what initiated this evolutionary process?”.  Certainly, oncogenes, tumor suppressors, and the like are a part of cancer pathogenesis, carrying the developing disease along.  But it seems to me that there is still a “first cause” of some sort that we have not put our collective fingers on.  Genomic instability is certainly key, but then what is the genesis of the genomic instability?  What are the inputs that kick this process off?  Efforts to answer these questions will move us closer to effective treatments for cancer and other diseases that may share these pathogenic processes.

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Tumor Heterogeneity, Revealed…

A very interesting and timely article on tumor heterogeneity was published in the New England Journal of Medicine today.  Gerlinger and colleagues from the UK used next-generation sequencing to look for heterogeneity across various regions of renal tumors and metastases in four patients.  They report that indeed there is a great deal of heterogeneity within individual tumor nodules–in fact, most of the many alterations to the tumor genome were not shared across all nodules.  Further, analysis of the pattern of mutations revealed branching evolution of the primary tumor and its metastases, rather than a linear pattern of progression of the cancers.

A couple of important conclusions suggested by this work:

  • Single biopsies of the primary tumor may give you a very misleading understanding of the cancer.
  • Cancer stem cells may not be what we thought they were, if they exist.
  • Confirms the adaptability of cancers by demonstrating convergent evolution of functional gene alterations.

None of what was reported is inconsistent with evidence from previous decades of cancer research.  It was work that really needed to be done and I’m happy it appears to have been completed in a careful, thoughtful way.

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An Academic—Industry Partnership to Study DTC Genomics

A GenomeWeb story today provides details of a study being performed by researchers at Brigham and Women’s Hospital and the University of Michigan on the motivations for getting and effects of DTC genomic testing. The study will look at the attitudes and motivations of 1000 people who order tests from 23 and Me or Pathway Genomics before testing. These results will be compared with the subjects’ attitudes toward their health and changes in their behaviors following testing to ascertain how people use genetic information.

Two interesting aspects to this study are the academic-industry collaboration and the window into social attitudes toward genetic information. The ability to complete this research will require the industry participants to cooperate, which in turn required give and take from both academia and industry to accommodate the needs of both parties during the planning process. These two groups are often at odds, so it is heartening to see a partnership that recognizes that both parties are motivated to make positive contributions to the greater health good. The road to this agreement is described in this paper by Lehmann and colleagues .

Clearly, the payoff for this study will be answers to questions around why people are interested in this type of testing anyway and what effect it has on their lives. A big concern from the health policy world has been that dispensing this type of information without expert interpretation might lead to a range of ill effects on the recipients. Happily, this so far has not been the case and for the most part I don’t believe ill effects will be observed in the future.

I am curious to see what the motivations for so-called “recreational” user are, if those can be identified in this study. Similarly, it will be interesting to infer from these results how seriously people take genetic information. My sense of it is that these results may reflect back in surprising ways on the usefulness of a variety of other genetic and genomic testing services, primarily involving the risks of disease. This study will hopefully provide a novel window into what we as a society really think of genomics.

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DTC Genomic Testing—What’s it good for anyways?

What is the fuss over DTC genomic/genetic testing all about anyways?  DNA is just a sequence of letters, isn’t it?  Lots of people are experiencing angst over the fact that these upstart companies would have the nerve to sequence part of people’s DNA for them.  I mean, it’s just a bunch of letters, isn’t it?

Seriously, I have to admit, I, as a molecular biologist, have experienced a degree of self-righteous indignation that these so called entrepreneurs would debase the field of genomics and medical genetics by offering to sequence anybody’s DNA for a price.  It seems beneath all of the effort and concern that has been invested in developing the field.  All of that hard-earned knowledge being sold off the shelf like a cheap tabloid.  That was the feeling, anyway, and I imagine some amount of that type of sentiment contributes to the resistance to the development of the DTC genomics field.

However, the reality is that those letters are attached to a lot of other information that may have health implications.  There are several serious genetic diseases (ironically, most discovered prior to the genomic era) whose sufferers (or carriers) traditionally receive genetic counseling to learn how to cope with the situation.

Beyond these known disease situations, the hype of the genomic age has led to lofty expectations for genomics.  Those letters are our shorthand for the substance (DNA) that gives us our individuality and which when altered is may give rise to disease, tell us who our relatives are, and potentially make us weller-than-well (if only we can change it a little bit).  We’ve bought pretty heavily into the idea that we are our DNA and therefore, revealing it is, in a sense, giving ourselves away.  There is an ever-growing body of genomic information that pins many hopes and dreams and futures to those four letters.  So, it’s not surprise that feelings run high when it comes to genomic information.

So, DNA/genes/genomics is loaded with expectation, but what’s DNA sequence information really good for when one takes a hard look at it?  How is it being used now?  We can start with a partial list of uses that have been found for DNA sequence information:

  • Disease risk assessment
  • Disease diagnosis
  • Preconception screening
  • Forensics
  • Genealogy
  • Recreation

The fuss that these upstart companies have created has revolved around health information for the most part.  That would be the first three items on the above list.  These companies are seeking to sell their customers their own DNA sequence information, along with an assortment of linked information regarding the health implications of the DNA sequence in question.  It’s the health information being sold along with the sequence information that has caused the kerfuffle with the FDA and the medical profession.  And, for some understandable reasons…

Long before we even knew what DNA was, enterprising companies and individuals were taking advantage of our sensitivity around health issues, selling remedies and other noxious (or inert) substances to solve health problems.  This profitable, but unethical, behavior was addressed through creation of the FDA, whose job it is to keep the nation’s healthcare resources safe.  So, here we have what might be called the modern day version of the snake oil salesmen (at least in the estimation of some): the DTC Genomics companies.  Not surprising, then, that the FDA might feel compelled to step in, as it appears they are likely do.  Similarly, many in the medical community have allowed as to how they would prefer that their patients not have access to their DNA information.  Also not surprising, since for known genetic diseases the medical profession has heretofore controlled this information  However, as it currently stands, the genomic profiles being sold by DTC genomic companies are pretty innocuous, so it doesn’t stand to reason to restrict the type of genomic information the DTC companies are selling.

My view is that we stand at a crossroads of sorts.  Down one road we regulate human DNA sequencing as a medical procedure, bequeathing control of the resulting information to specialists licensed to dispense that information in carefully predetermined ways.  This is a suitable model when the dispensing requires extensive training to avoid injury to the receiving party, as in the case of prescription drugs or cardiac catheters.  For genetics in the current information-rich environment and age of patient empowerment, I believe that there are a limited number of situations in which harm would come to a person who knew their own DNA sequence.  And, even those cases (e.g. Tay Sachs disease) it is questionable if the actual harm is sufficient to bar access except under carefully controlled conditions.

The other road might be one in which one can obtain the sequence of their genome, if they are so motivated and can afford it.  It is likely that reasonable quality services will be available to provide this information soon (currently there are concerns about quality with many of the providers; note to DTC genomics companies: you would do well to pay attention to the quality of your sequencing if you want to survive).  The latter three items on the list above would be supported by relatively simple, low hurdle access to sequencing services.  In fact, my guess is that FDA regulations or no, in the near future a motivated person will be able to get their genome sequenced.  Somewhere.

My concern  is what we might lose if we over-regulate DTC genomic testing.   The latter three items on the list have emerged in recent years.  What else might be added to the list in the future?  What uses for DNA sequence data are not on that list?

What is DTC genomic testing good for anyways?  I don’t think we know the answer to that question yet.  Should we follow the Silicon Valley paradigm, let go of the information, and see what millions of “users” out there do with it?  Should we “crowd source” genomics?  Maybe there is someone out there with a marketing degree, a penchant for spreadsheets, and the interest in genetics who can offer a creative solution for the problem of missing heritability of SNPs.  Maybe a user group will surprise us by producing a creative solution to one or another vexing biology or health problem that has stumped the collective brain power of us professionals?  We may not know what DTC genomics is good for unless we give it a chance.

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Testing DTC Genomic Testing I

Now that we’ve all gotten over the shock of being able to order a genetic test through Amazon.com, we can begin to actually ask some useful questions about DTC genomic testing and its utility.  Not much is really known about how useful it is.  However, in the tradition of Hippocrates, the first question we must ask is “is it harmful?”

The medical research community was all over the task once the DTC genomic testing services emerged from the intellectual garages of Silicon Valley and elsewhere and hit the streets.  Two studies of note asked the question above, using Navigenics’ service as a model.  The first paper was published by Bloss and colleagues in the New England Journal of Medicine in February of this year.  Just last month, James and colleagues published another study of the effects of DTC genomic testing in the Proceedings of the Mayo Clinic.  Neither paper reported any untoward effects of genomic testing under these circumstances on the test population.

More studies of DTC genomic testing are in the offing, I’m sure, in addition to the commentary and other reports on the technology so far published.  Now might be a good time to take a longer look and ask some of the interesting questions about DTC genomic testing, what it means, and why it created such a commotion.  I am in the process of shifting through many of these reports and opinions and will write another post soon on the subject.

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Are most published research findings false?

Many people are aware of the work of John Ioannidis regarding the analysis of research findings and the conclusions drawn from those analyses.  In particular, these concepts were described by him in a paper published in PLOS Medicine in 2005 is apparently the most downloaded article from that journal.

I’ve had this article on my mental favorites list for some time now.  I am finally putting a few words in print about it mostly to put a stake in the ground on this issue because I believe it is an important one in this era of high volume research reporting.  In short, I agree with the article’s main conclusions, although I might phrase it as “most published biomedical research conclusions are not true”.  This is not to say I think there is some conspiracy or that statistics are useless.  To the contrary:  statistics is an enormously useful field of applied mathematics.  I also think a great deal of very good research is being done in labs and clinics around the world by very dedicated and smart researchers.

My concern over the veracity of biomedical research and how these results are reported stems from the nature of statistical models and test versus how they are interpreted and reported.  Within that discussion is another around the unspoken assumptions underlying both our biological and statistical models.

Perhaps the stickiest issue for me is the use, or misuse, of p values in many published studies.  Without getting too long-winded about it, far too often the p value is used all by itself and given the status of a “stamp of approval”.  Using a p value in isolation (i.e. p=0.001 therefore I won!) is ignoring a lot of important information.  What type of test did you “win”?  What distribution of p values for this test did you assume?  Are your assumptions correct?  Did you keep testing data until you found the p value you were hoping for?

Fortunately, I think the wider scientific community is waking up to the deficiencies in the most commonly used statistical analysis scenarios.  This recent article from Genomeweb does a nice job describing the basic appropriate role for statistical analyses in biomedical research.  An important distinction pointed out in their article is that statistical significance and biological (or clinical) significance are two different things.  When we rely on statistics to identify important relationships within a vast ocean of information, it is all the more important to understand what these mathematical tools are telling us.

As the wise scientist once said, “Never assume anything other than a 4% mortgage.”  I mentioned assumptions above in the sense of statistical models; assumptions also come into play in experimental design.  My sense of it is that these assumptions are usually underappreciated or perhaps even ignored.  The danger, of course, is that incorrect assumptions, statistical or experimental, can invalidate the results and conclusions of any research.  Often these assumptions difficult to verify, which we might be able to cope with, if we knew what these assumptions were.  Unfortunately, they are not part of the standard scientific reporting paradigm.  This recent article in PLoS Computational Biology sheds some light on the issue of reporting experimental assumptions.  Again, by bringing the issue to light there is hope that we can begin to change our science reporting procedures to incorporate some discussion of assumptions.

I find it reassuring that these discussions about accurate analysis and reporting of scientific research are surfacing.  Opening up communication about these critical issues will greatly enhance our ability to navigate through the ocean of biomedical studies available to us.

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Genomic Test for your Kid’s Sports Ability? Oh, Please!

The US FDA just sent out more letters to genomic testing firms asking them to explain why their testing kits should not be regulated.  The companies in question (and their target market) were Lumigenix (disease predisposition), American International Biotechnology Services (AIBiotech, workout optimization for athletes and also disease predisposition), and Precision Quality DNA (PQDNA, disease predisposition and drug response).

Based on the blogosphere reaction, the testing of genomic influences on athletic performance drew the most attention.  I don’t know much about genetic influences on athletic performance, but I don’t think anyone else does either.  Hence the reaction to such a product—is there really any value there?  I already have to submit a copy of my son’s birth certificate to enter him in certain sports tournaments.  Am I also going to have to submit his genetic profile so he can join AYSO?

For all three it appears to me that the FDA was pretty reasonable in exercising its mandate to protect the public health by blocking unreasonable medical claims for products.  It’s unfortunate for those companies that are trying to do the right thing by backing up their genetic testing services with real data; they may well have to carry the burden of federal regulation soon.

 

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Failure of the Genome?

I recently read an article written by Jonathan Latham in the Guardian (UK) online with the title, “Failure of the Genome” (credit to Genome Web for pointing the post out to their readers).  Following the eye-grabbing headline, the article goes on to posit that the Human Genome Project has not turned up much of use.  Indeed, the author asserts that there is scant evidence supporting the genetic underpinnings of disease paradigm.  To a geneticist or one of the many others who have backed the various genome projects, this is provocative indeed.

So, why did this provocative headline catch my eye?  I have to admit, I am one of those who have become weary of seeing the “Gene For…” headlines ad nauseum over the last couple of decades, only to see those claims vanish into the twilight of yesterday’s news time and again.

The magically vanishing claims of genetic causation that show up daily certainly have jaded even a dedicated molecular biologist like me* to an extent.  As such, I can understand how this pattern of hype of research results followed by disillusion when the claims quietly die would dishearten others who see these stories.

So, maybe what grabbed me was the sense that we, as a society, have swallowed the genetic-cause-of-disease hype hook, line, and sinker—and this article is evidence of rising discontent the emptiness of those hyped promises that come in company and university press releases.  The real story about genes and disease is more complicated than will fit in the easy to digest news bits that are our common food in these information-intense times.

I hope that we scientists will recognize this backsplash as a signal to examine how we communicate our science.  What I most value in the scientific enterprise are the truthfulness and credibility that are a part of this culture.  I hope we will work to preserve these qualities.

 

*I come to this as a molecular biologist with a couple of decades of experience doing research in oncology, in particular, the role of oncogenes in the development and progression of cancer.  Based on my own hands-on experience in trying to understand the role of genes in a disease, I’d be hard pressed to simply dismiss genetic variation as a factor is disease causation, as Mr. Latham does.  It is pretty clear to me that variation in genetic makeup leads to variation in phenotype, some of those phenotypes being what we call “disease”.

 

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