Tuesday, November 26, 2013

My Take on the FDA Warning to 23andMe

NOTE (8/5/2020): As I gained more experience finding problems that were not clear until after 5-10 years of research, I looked back at this and I would not have completely agreed with earlier responses.  So, I have separated my first response (Response #1) and additional responses (Response #2).  I have also started to keep a change log, for updates after this point.

Getting Advice About Genetic Testing

I have recently participated in a forum discussion on Biostar about the newest warning to 23andMe from the FDA.  I think my responses will be of interest to a broader audience, so I have copied them here.  If I end up contributing more to the Biostar discussion, I will update my blog post as well.

Comment: The majority of published reactions seem to miss what the FDA's major issue is: about marketing and describing the service.

Response #1: Yeah, I agree that the wording in this warning focuses mostly on marketing.

However, the FDA has previously tried to shut down DTC genomics companies (including 23andMe) and the 3rd paragraph seems to mostly focus on the accuracy of the test. The carrier status report should really be OK for diagnosis (and I think many of the specific associations mentioned in that warning are also pretty well established). Now, there are some caveats to some results like deciding how to combine independent SNP risks and explaining the difference between a mutations that guarantee onset of a disease versus modulate risk (which may only have a modest impact on risk in many cases). I personally think 23andMe does a decent job of this already, but I'm sure there can always be room for improvement.

In other words, my understanding is that the problem was primarily with direct communication with the FDA regarding technical benchmarks that would justify marketing claims (and I think the FDA is supposed to provide permission based upon this data prior to advertising). This certainly relates to communication with customers, but I think delays in formal responses to the FDA from 23andMe were the primary problem.

Response #2: In retrospect, I don't think I should have used the phrase "shut down".

I might add additional thoughts, but this was the main thing that jumped out when I re-read the blog post.

Concern: There is at least one report of an individual with an inaccurate 23andMe report (click here to view).

Response #1: Make sure to read the entire article.  Once the bug was reported, it was fixed and the report was updated.

Response #2: Errors need to be made clear to customers.  You can see some notes like this among this collection of blog posts (which includes submission of multiple FDA MedWatch reports), but I don't believe any of this was made clear to other customers.

While a lack of confidence is sometimes necessary to communicate, it does need to be communicated.

There can also be negative consequences.  For example, if the trace for the automated Sanger sequence was not checked, then sequencing error could be a false positive for a pathogenic mutation.  If this was not caught before action was taken (which could be something like an unnecessary mastectomy), then permanent damage could be caused from providing a result prematurely and/or inaccurately.

That said, I don't want to over-emphasize the potential harm, and I think helping citizens become engaged in problem solving and critical assessment would be valuable (if genomics data / hypotheses were used for that purpose).

Concern: The issue isn't the bug. The issue is that 23andMe is offering a product while making claims about how customers can use results for improved medical care. Medical professionals and should be in charge of offering medical services.

Response: I agree that communication with customers is important and some customers may not have a good sense of what it is like to be part of a research project. It is possible that this is something 23andMe needs to work on.

However, I think the best solution is not to get rid of 23andMe, but rather help improve communication regarding the confidence of results. For example, I wrote a blog post about one possible solution after a previous FDA warning was issued:


Also, I don't think this is a typical result. For example, here is a link to my results as well an article from Lifehacker (from someone with much less experience with genomics research). I'm sure I've seen more, but these are what I could think of off the top of my head.



Plus, I think an unfortunate reality is that this sort of thing will happen from time to time. I think pretty much all diagnostics will suffer from some degree of false positives, false negatives, and/or human error. I know I constantly have to update the bioinformatic programs that I design (for what I would call "research grade" analysis) - especially when hunting down bugs that are only apparent when analyzing a small number of data sets.

Concern: The fact that it turned out to just be a bug is one thing, it's pretty bad but they fixed it, but even if it had turned out to be true, it's still horrific. Imagine being sent an email saying, "Hey, you're going to get progressively disabled then die young," and no further information about what the condition is and how it's going to affect you, no kind sympathetic face offering you tissues and advice and options. This guy did his research and turned out to be fine, and that's great, but how many people fall into deep depression on getting this news? How many people kill themselves? You can't give out this kind of potentially devastating life-altering news in an email.

Response #1: For some people, I agree this may not be the best way to communicate results. This is probably why 23andMe adds an additional step for viewing results like this that are not present for non-medical and non-predictive results. If you aren't prepared to view results on-line, then I would probably recommend either not getting a 23andMe profile, not viewing that portion of the results, and/or contacting a genetic counselor to review the results with you. For example, my 23andMe report indicates that I am a carrier for cystic fibrosis and they provide a link on how to talk to a genetic counselor on that page:


That said, I think the concern overall is an over-reaction for the following reasons:

1) There have been several publications showing that most people have no problem responding to DTC genetic testing. I can't list all the publications off the top of my head, but here is a summary of one such article:


2) In general, the accuracy for the DNA sequencing portion of the tests (currently via an Illumina SNP array) is pretty good. For example, the FDA has recently approved Illumina sequencing for clinical application. I'm also pretty sure 23andMe has checked the accuracy of the array by comparing normal 23andMe clients to the results from people who participated in the exome sequencing pilot. That said, there is a difference between the interpretation for the carrier status results (which is relatively straightforward) and all of the other results, and my understanding is that failure to communicate these results to the FDA is one of the legitimate complaints from the FDA letter.

3) I think people need to be careful and critical in all cases. For example, let's say I had a wife who was also a cystic fibrosis carrier (identified via 23andMe) and we were thinking about kids. The first thing I would do is verify the result. For example, I could order a Counsyl test from a doctor (which might be a good alternative for some people instead of 23andMe, although I think you might still be viewing your results on-line) to verify that we were in fact both carriers. I wouldn't immediately run to an in vitro fertilization clinic. Plus, medical professionals can make wrong calls too. Also, to be clear: I have family members who are confirmed cystic fibrosis carriers, as determined by standard testing.  So, I think the probability of this being a false positive is very low, but I would always want to tread carefully.  This has certainly happened to me, which at least one time delayed hospitalization for a very serious infection. This is not an attack on the medical establishment: there is a reason I went to see the doctors in the first place. However, I think the actions made by this individual were spot on, regardless of whether something is FDA-approved and regardless of whether a result comes from a person or a computer: if something doesn't sound right, you should look into a second opinion, independent research, etc.

Response #3: As an update to 3), I later submitted my samples to multiple companies.  With the raw data, I would confirm that I am cystic fibrosis carrier.  However, multiple companies said that I wasn't a carrier.  So, I think having raw data and taking time to evaluate results is important.

CommentThere is now a class action lawsuit against 23andMe: http://gigaom.com/2013/12/02/23andme-hit-with-class-action-over-misleading-genetic-ads/

Response #1That is unfortunate.

Response #2: While I hope issues can be resolved outside of court, I now agree that 23andMe (and AncestryDNA) ads can be misleading.  As one example, I had/have serious concerns of advertising Airbnb destinations (as mentioned in this blog post).

While I usually kept the previous responses, I thought this paragraph should be changed (hence the different font color).  Essentially, I think the link below is worth reading, but my impression is different.  I still think it was important to change the title (to avoid exaggerating the problem).  However, I think important points were also raised and I apologize for not sufficiently appreciating that before:
I'm still hoping that most conflicts can be settled out of court (if that is still possible at this point). At least this provides a list of specific claims that I hope 23andMe will directly address to customers in an official statement - at least they can reference a plethora of 3rd party experts who can generally back them up. I certainly think they made bad choices with the timing of advertising and providing terse official responses, but I don't think that should be a $5 million mistake (especially for a service that I assume is being provided below cost)
Update: I also have put together a survey on this topic. If you can fill out and/or distribute the survey, I would appreciate it!

Change Log:

11/26/2013 - public post date
8/5/2020 - start keeping change log with updated responses
8/6/2020 - continue to add revised responses

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