Questions About Genetic Testing

NOTE: Getting Advice About Genetic Testing

I've recently been asked some questions about genetic testing, some of which I think are worth mentioning in a public discussion (although please see the note above if you are interested in getting specific recommendations):

1) How can I use my DNA sequence to inform my decision making about reducing my risk of getting a disease?

In many cases, I think the actions that you can take to reduce disease risk are relatively generic (exercise, eat lots of fruits and vegetables, etc.), and these are things that you should do regardless of your genotype.

That said, there certainly are some circumstances where very specific action can be taken, based upon your genome sequence.  I am not personally aware of all such examples, and I would recommend talking to a medical professional (such as a genetic counselor) for more information.  If this is the only type of information that you wish to learn about your genome, then you may only benefit from determining the sequence for a small portion of your genome (and your family history can guide the likelihood of needing to perform any genetic tests in a clinical setting).

2) How does Promethease compare to the health reports from 23andMe?  Does Promethease mostly focus on rare mutations?

Promethease is based upon annotations that come from SNPedia (similar to wikipedia, but specifically for mutation annotations).  So, I would expect the content would depend on whatever information is entered by volunteers.  Given the amount of information that I see from by 23andMe data (which is mostly common variants), I would say it contains a large amount of information on common variants.

When I first ran Promethease, I remembered mostly seeing risk annotations (which you can see in my old post, comparing my top 23andMe risk associations), and I didn't remember seeing anything like the carrier status report.  For example, I didn't remember seeing anything reporting me as a carrier for cystic fibrosis, which is an example of a 23andMe result that was in good concordance with my family history.  However, I went back to check my specific mutation (394delTT), with a probe ID i4000313.  This particular probe ID makes it a bit harder to match the mutation.  However, if I Google the probe ID, I can see that is is included in SNPedia but without a detailed description.  If I look up 394delTT in ClinVar, then I can get more information about this variant and I can see that it corresponds to rs121908769.  If I then look this variant up in SNPedia, I can see that it provides some information from ClinVar (although there is nothing in the brief main text for mentioning cystic fibrosis), but I don't see it among any of the "cystic fibrosis" variants in my old Promethease report.

However, to be fair, I wanted to re-run my sample through Promethase to see if the reporting system has changed and/or confirm that it now recognizes this mutation in my data.  It appears that a many new features have been added within the last 3+ years, such as a more interactive interface (viewed by clicking "UI version 2" in the downloadable report). Additionally, I can tell that the "medicines" and "medical conditions" have been expanded to include more SNPs.   However, it still don't recognize my cystic fibrosis carrier status, so it can't simply considered a replacement for the old 23andMe report.

Also, in general, the information available in Promethease tends to be terse, and it won't contain the same level of detail for explaining basic concepts as would have been provided by the old 23andMe health report.

3) More specifically, I do not wish to see a doctor in order to obtain my genetic information.  Also, I want something clear and easy to understand, which doesn't require doing any additional research.  What are my options, now that 23andMe no longer offers health reports?

I am not aware of any direct-to-consumer test that provides information that is comparable to the old 23andMe health reports, and I am not aware of any tool to analyze your raw 23andMe data that will reproduce your the old 23andMe health report (especially not with all the details to help make the results easier to understand).  I believe that even Illumina's Understand Your Genome program requires meeting with a doctor to draw your blood, conduct a predisposition screen, and discuss your results.

Perhaps more importantly, I think it is worth emphasizing that the health reports previously offered by 23andMe were not really a single report: they were updated periodically as new findings were published in the genomics literature, so your estimated risk would change over time for many traits.  This should be generally true for any tool connecting you to the genomics literature, as also demonstrated for the Promethease example above.

If you were only interested in the subset of results that are unlikely to change, I think you would probably have been most interested in the carrier status reports (and a handful of the other reports).  There are tests like Counsyl that I would expect to probably be similar to the the 23andMe carrier status results (and it is something that I would want to check out, if I was planning on having a child), but I believe that you can only get that test through your doctor.  However, this is just one example: I would recommend talking to a doctor or genetic counselor if you want more specific guidance.

In my opinion, I am most uncomfortable with the request to get a result that "doesn't require doing any additional research".  Critical thinking and being able to synthesize your own opinion from multiple sources of information are important skills that should be part of everyday life, and I think "additional research" is especially important for tools designed for "research and educational purposes" (including 23andMe, Promethease, Interpretome, etc.).  For example, clinical action may be limited because 1) all the genetic influences of disease risk are not known, 2) ways to mitigate genetic risk may not be known, and 3) one current limitation to low-cost options like SNP chips is that you aren't measuring your entire genome sequence (so, some important sequences may not be covered).  This might be a problem for some people, but I think it is still OK for many people.

In other words, there certainly have been some cases where people discovered important findings from their 23andMe reports that were worth verifying in a clinical setting, but I think most 23andMe customers took no medical action based upon their reports.  Most importantly, "no medical action" need not equate to "dissatisfied": I would personally fall the category of a customer who was "very satisfied" yet has not changed by behavior because of any of the results.  I think trying to understand how your biology is influenced by your genome sequence is a life-long goal that will probably never be fully realized, but I think there is value in being able to understand on-going genome research through the context of your own genome.

Getting Advice About Genetic Testing

I recently received a call at work from an individual asking for advice about genetic testing.  While I welcome questions and comments on my blog posts, I don't think this was an appropriate course of action.  I don't think it is a huge problem (this is the first time this happened in the 3+ years since I wrote my most commonly viewed blog post), and I think this individual raised some interesting questions.  However, I think it may be important provide a brief description of myself and the role of my blog:

 I am an analyst that often studies (de-identified) patient samples for biomedical research, and it is probably safe to say I have an above-average knowledge about genetics.  However, I am not a medical professional, and I never provide consulting about genetic testing at any point during my job.  In fact, a large portion of my research involves projects that do not look for mutations in a subject's DNA sequence.  In other words, everything I write on my blog about genetic testing is my own personal perspective, independent of any professional responsibilities.

Of course, that leaves the obvious question:

Where can I find someone to discuss genetic testing options?

I would recommend contacting a genetic counselor if you wish to talk to somebody one-on-one about genetic testing options and what action can be taken as a result of those tests.  The National Society of Genetic Counselors has a tool to find a genetic counselor near you:

http://nsgc.org/p/cm/ld/fid=164

Again, I should emphasize that I am not a genetic counselor myself: if you are genetic counselor or medical geneticist with a better recommendation, I would encourage you to post a comment to this blog post.

How and Why the FDA Should Allow DTC Genetic Testing

At the beginning of this month, the FDA extended the period to submit public comments about Direct-To-Consumer (DTC) genetic testing to the Molecular and Clinical Genetics Panel of the Medical Devices  Advisory Committee (referencing docket ID FDA-2011-N-0066 at http://www.regulations.gov).  For more information on this topic, please check out this post from The Spittoon (the official blog for 23andMe).

I just submitted a comment to the FDA (which is essentially a shortened version of this blog post).  You can currently view my comment here using Google Docs, but I do not currently see the posting on http://www.regulations.gov (I will work on verifying that the comment was successfully uploaded).  In fact, there were only a few comments posted after the original 3/1/2011 deadline, and I do not see any new comments posted after the extension of the comment period that occurred on 4/1/2011.  If you have not already done so, please submit a comment before the new deadline on May 1st!

In many ways, I think DTC genetic testing companies are similar to medical websites like WebMD (which is an idea I first remember seeing in this blog post comment).  I personally think it would be a great disservice to society if websites like WebMD, Mayo Clinic, and MedlinePlus were banned because they provide medical advice to the public without consultation with a physician.  Likewise, I also think it is very important that people be able to learn about their own genetic information without having to consult a physician (although I would certainly encourage people to seek advice from medical experts if they feel the need to do so).  Although all doctors do not agree that patients should have access to DTC genetic tests, there are also some doctors that dislike WebMD.  I do not believe this is a valid reason to ban either type of medical information.

I want to emphasize that I do not oppose any sort of FDA regulation.  For example, companies that intentionally mislead people should be penalized (as one example, check out this post on My Gene Profile by Daniel MacArthur).  However, I do not think the FDA should ban companies who are transparent in their actions and are basing their analysis of published, peer-reviewed scientific research.

I think there is sufficient evidence to show that most people will have reasonable reactions to their results (for example, check out this research article in New England Journal of Medicine).  However, I think it might be helpful for the  FDA to help classify which test results clearly require medical action and which ones are "research" grade tools that connect people with findings in the medical literature.  In an earlier post, I discussed how a "3-tier system" might be able to help accomplish this.  Essentially, we currently do have "clinical" tests and "research" tests, but I think formalizing some sort of system to distinguish between such tests could be useful (especially if it helps provides a way to maintain DTC genetic testing without the need to require physicians act as a gatekeepers for this information, or if it prevents these tests from being outright banned).

In general, I think it is important for individuals to have access to a variety of opinions in order to think critically when making medical decisions.  It is not good to blindly trust any source of information - whether that information comes from a doctor, a DTC genetic testing agncy, a government regulatory agency, or a scientist (like myself).  I strongly believe that people should have access to second opinions about their genetic tests (through tools like Promethease).

I think the FDA could also potentially help improve genetic testing (for both DTC and non-DTC tests) by helping provide people access to secondary sources of information.  For example, I think it would be fine for the FDA to force companies to allow users to export their data in a standard format in order to allow people to easily get second opinions about their genetic testing results.  Strictly speaking, I don't think this is necessary - for example, there are 3rd party web apps that help users learn more about their 23andMe results (such as this Firefox app), and Promethease already helps users search for annotations from SNPedia (although there is a $2 fee if you want your results quickly).  However, I don't think it would hurt to have a standard format that applies to all genetic testing companies.

In fact, a standard format for sequence data from genetic tests could provide a useful framework for a collaboration between the FDA and NIH to fund development of of a free tool for people to analyze their genetic information.  For example, MedlinePlus is an excellent resource provided by the NIH, and I think it could be really cool of the FDA would work with the NIH to help people analyze their genetic information similar to the way MedlinePlus provides traditional medical advice   If such a collaboration were to take place, then I think it would also be fair to require genetic testing companies to provide links to this 3rd party tool (as well as other tools, if they choose to do so).  This could be helpful both in terms of helping people think more critically about their results and I think it could be a good way to fund research on how to best convey genomics research to the general public and incorporate publicly available data into a single risk assessment provided by this free, 3rd party tool.

Update (6/20/2020): I wrote this post before I started adding change log entries.  However, I added a note because my opinions have shifted somewhat since I originally wrote this blog post.  For example, you can see several FDA MedWatch reports that I have submitted within the collection of posts linked here.

Essentially, I think I have better appreciation for the harm that can be caused if a result is rushed to the public, especially if information is distributed to a large number of people (such as 10,000s or 100,000s of customers).  I still believe that situations where something partially effective that still works better than a placebo (or has non-trivial predictive power) should be thought of differently than highly effective solutions or completely ineffective solutions.  Indeed, you can see some non-genomic reports in my PatientsLikeMe post, at least one of which I also submitted as an FDA MedWatch report for side effects.

I think setting the right expectations can help, but I thought the problems that I didn’t notice before were sufficiently important that I needed to add something to this post.

I also think it is important that genomic risk calculations can be validated in independent cohorts, which makes transparency and on-going quality assessment important.  For example, I still believe that publicly available information is important, which means that you can have access to it with or without a physician.  Even if there are consent limitations that require controlled access (or prohibit carrying out the experiment in the first place), I think maximizing specialist access to raw data (with accurate documentation of data sharing) is still important.  If you look at the cystic fibrosis post, you can see that free and open feedback from a Biostars discussion helped with re-analysis of my raw data.

Benefits to a 3-tier system for DTC genetic testing

The popular genetic testing company 23andMe has two rankings for genetic associations present in the scientific literature: Established Research Reports and Preliminary Research Reports.  The relatively recent GAO report on genetic testing claimed that 23andMe provided "reports that showed conflicting predictions for the same DNA and profile, but did not explain how to interpret these different results" (and the response from 23andMe can be viewed here).  However, I think this system provides a useful basis to improve education about genomics research and genetic testing.  In fact, I think it would be even better to provide 3-tier system to describe genetic associations.

In particular, I think genetic associations can be classified as "Based upon Preliminary Evidence," "Based Upon Reproducible Evidence," or "Therapeutically Useful."  In this case, I would consider "Reproducible" associations to be equivalent to 23andMe's "Established Research Reports."  I would consider "Therapeutically Useful" associations to be those that have been proven useful in terms of significantly reducing patient mortality or morbidity.

The "Therapeutically Useful" classification is important because there could be many reasons why individuals with a particular mutation may have a increased risk of dying from cancer that is statistically significant, but information about that particular mutation may not be important for informative for making medical decisions.  For example, models for genetic predisposition may be complicated for certain diseases, and it may be necessary to incorporate currently unknown information about other mutations in order to provide an accurate estimate of risk to develop a given disease.   Also, there are cases where environmental factors may be more important than genetic factors.  And the list goes on.

In practice, I think the FDA could play a role in helping define the third category of genetic tests, and I can think of at least two ways to implement this.  First, genetic testing companies could post some sort of "FDA-approved" icon for tests that have shown to produce positive results when applied in a clinical setting.  Second, the FDA could post a listing of genetic tests that have been proven useful through clinical trails and provide a list of appropriate treatments that correspond to a given test result.

There are benefits to having access to genetic information that doesn't necessarily meet the criteria for a "Therapeutically Useful" test.  For example, there may be no "FDA-approved" diagnostic for a particular problem and an experimental prediction may be the best possible resource.  Furthermore, the FDA has indicated that it does not see a need to regulate the release of "raw genetic information," and it is acceptable to communicate information about genetic associations though other means.  For example, the FDA would never censor an article in the New York Time about a new discovery or preliminary result.  Genetic tests that are"Based upon Preliminary Evidence" or "Based Upon Reproducible Evidence" are basically indicating that "Hey, you have this mutation that has been described in the scientific literature."  If it is too confusing to provide separate predictions for each tier of genetic associations, then genetic testing companies should at least be able to provide a list of publications describing a mutation of interest (and possibly provide a brief summary of the findings).

Information from DTC genetic testing can also fundamentally increase understanding about human genetics and contribute to scientific research, as indicated by 23andMe's publication in PLoS Genetics.  In fact, 23andMe could actually help establish "Therapeutically Useful" tests if customers could upload clinical information that is directly incorporated into their models.  Likewise, companies like PatientsLikeMe could help test the therapeutic value of genetic tests if patients could upload their genetic information

In general, I think individuals should take a much time as they reasonably can to research a topic prior to making a life-altering decision.  Even if a diagnostic is 98% accurate, what if you happen to be in the minority that gets a false-positive?  Even well-established tests can have false positives.  Important information can be gained from independent tests, consulting with a physician or genetic counselor (or getting second opinions from multiple professionals), or even talking to friends who might have went though similar situations.

Although I understand that a "3-tier" system for genetic testing may be confusing for people at first,  I think this system could be a useful tool to educate the public about genetic testing and encourage individuals to take a more active role in making medical decisions.  In fact,  a recent post by John Timmer concluded with the suggestion that heavy regulation of the DTC testing industry will probably not be necessary if a sufficiently large proportion of the general public took the initiative to better educate themselves.