
One DNA test said he was likely to get Alzheimer’s, the other said he wasn’t - ramzyo
https://www.nytimes.com/2018/09/15/opinion/sunday/23andme-ancestry-alzheimers-genetic-testing.html
======
m3nu
Ancestry.com is known to report one of the ApoE-SNPs wrongly. I wouldn't be
surprised if this happens for more rare genes as well.

> Word of caution to those with data from Ancestry.com: in our experience,
> based on data in OpenSNP and from Promethease users since 2006, Ancestry
> data always reports rs429358 as (T;T), even for people who's data from other
> sources indicates they are (C;T).

[https://www.snpedia.com/index.php/APOE](https://www.snpedia.com/index.php/APOE)

------
gwern
> “It’s not about the issue being half-baked,” the doctor replied, “but what
> the heck do we do about it, once we know, other than create high anxiety?”

Loads. Are you seriously telling me that you can't think of _anything_ useful
to do with this knowledge? (What about if he wants to have kids?)

> The doctor referred Mr. Fender to a geneticist, but it turned out he did not
> see patients under 50 who were not symptomatic and had no family history of
> the disease.

> Mr. Fender then tracked down Jill Goldman, a genetic counselor specializing
> in dementia at the Taub Institute at Columbia University Medical Center, who
> described a multistep process of counseling and confirmatory testing that’s
> been the standard of care for 25 years. She typically serves people at high
> risk of inheriting a disease, and insurance usually covers both the
> consultations and the tests. But it was unlikely to cover the costs in the
> absence of family history. “It was like a chicken-and-egg thing,” Mr. Fender
> observes. “I needed a medical test to prove to them that it was real, but I
> couldn’t get a medical test until I could prove to them that it was real.”

> Meanwhile, he happened to see a holiday special — $69 — for Ancestry’s
> genetic risk test.

There are problems here, but they're not with 23andMe or Ancestry.com, I don't
think.

~~~
Gatsky
Really? You don't see a problem with these companies selling tests to people
and then dumping the cost of confirming the result and dealing with the
implications on the already strained healthcare system? Meanwhile 23andMe
makes billions selling the data to pharma?

~~~
gwern
I don't because 23andMe didn't flag it in the first place, disconfirming it
was an order of magnitude cheaper than his interactions with the supposed
adults turned out to be and didn't involve any catch-22s or bullshit reasoning
(a geneticist should know that family histories can be wrong and de novo
mutations exist, and anyone with 2 brain cells to wire together should realize
the incredible value of learning you have early-onset AD rather than
paternalistically dismiss it as useless data), and the DTC companies are
approaching 10 million customers with few major issues - not that this could
be called a major issue in the first place.

> implications on the already strained healthcare system?

The healthcare system didn't do squat. That's kind of the problem here. In
fact, if we're going to discuss the system as a whole, I would point out that
not sequencing everyone is immensely costly and a major failing of the
healthcare system, as testing would pay for itself just in terms of better
dosing of drugs like warfarin. There shouldn't even be a question of learning
whether you have early-onset AD, it should already be known.

> Meanwhile 23andMe makes billions selling the data to pharma?

They don't. The deals are in the low millions as far as is publicly known (and
if you're referring to GSK's recent _investment_ in 23andMe, that wasn't a
sale). And if they are, it's not clear whether that makes 23andMe even net
profitable (they're at >$1b in total VC), and even if they have revenue, that
doesn't mean their investors have made 'billions', and finally, if they did,
good for them, because that means they created value by subsidizing DTC
testing for almost a decade, cut through the regulation, and created a large
useful database on par with the UK Biobank, which wouldn't've happened
otherwise. (If you don't believe me, ask someone how useful the Million
Veteran Project has been compared to 23andMe or UKBB; or just do a site search
on biorxiv.org...)

~~~
Gatsky
You haven't stated the population risk of having a pathogenic de novo PSEN1
mutation. This would be an essential preface to whatever argument you are
trying to make about the case described in the parent article.

'few major issues' is a liberal interpretation of being shut down by the FDA.
Besides, nobody is measuring the impact of the test, so how do you know there
are 'few major issues'?

> not sequencing everyone is immensely costly and a major failing of the
> healthcare system

I do cancer genomics in my day job. I would not agree with this comment on any
day of the week at the present time. The problem with 23andMe and their ilk is
it just isn't that useful. Warfarin use is being phased out anyway, because of
the many non-genetic causes of variability and the availability of drugs with
more reliable pharmacokinetics. This same principle applies to the vast
majority of serious medical conditions - lifestyle factors greatly outweigh
any genetic component.

But the biggest problem with acting like 23andMe is a useful test is they
don't actually do a proper test for the most common genetic condition that
leads to a serious condition with high penetrance - BRCA1 and BRCA2 mutations
and breast and ovarian cancer. They don't do a proper damn test, they just
test 3 out of the thousands of variants in the gene. Why do you think that is?
Why don't they do a proper version of the most useful and important test,
which can actually be used to prevent the patient getting cancer? The related
question is - who benefits from 23andMe testing? The company or the 'Me'?

Re the 'billions', which of the following is more likely:

\- VCs have given 23andMe >$1b in total because they think it can make
multiple billions by selling the data \- Any other reason

~~~
gwern
> You haven't stated the population risk of having a pathogenic de novo PSEN1
> mutation.

The population prevalence of any early onset AD is, and always will be,
extremely low because of its pathogenicity, just like any other gene which is
terminal with ~100% penetrance. The prior probability will be low, even
without checking, and the posterior won't be large either for the usual
Bayesian reasons. I shouldn't need to state this about the population risk, it
should be obvious, especially to a cancer genomicist. Unless you want to argue
that the mutation in question is very common...?

> 'few major issues' is a liberal interpretation of being shut down by the
> FDA.

Being nearly shut down by the FDA is no one's problem but 23andMe's. I was
actually referring to unwanted discoveries about family secrets, which are the
major downside of 23andMe testing. (Infidelity is a good deal more common than
early-onset Alzheimers.)

> Warfarin use is being phased out anyway, because of the many non-genetic
> causes of variability and the availability of drugs with more reliable
> pharmacokinetics. This same principle applies to the vast majority of
> serious medical conditions - lifestyle factors greatly outweigh any genetic
> component.

'Warfarin is being phased out' is another way of saying 'warfarin is still
used', and the uses go well beyond just warfarin
([https://www.biorxiv.org/content/early/2016/07/23/065540](https://www.biorxiv.org/content/early/2016/07/23/065540)
covers a number of other drugs, 2 years ago), the uses only increase with
time, and of course there's a chicken-and-egg thing here: drug response can't
be predicted without large datasets, and large-scale sequencing supply will
induce its own demand. (Just like how the UK Biobank's results induced even
more interest in genetics.) Many other things can be usefully predicted and
PGSes are increasingly of clinical utility
([https://www.gwern.net/docs/genetics/heritable/2018-khera.pdf](https://www.gwern.net/docs/genetics/heritable/2018-khera.pdf)
[https://www.gwern.net/docs/genetics/selection/2018-torkamani...](https://www.gwern.net/docs/genetics/selection/2018-torkamani.pdf))
and they add onto 'lifestyle factors' prediction, considerably, there is no
reason to use only one.

> They don't do a proper damn test, they just test 3 out of the thousands of
> variants in the gene. Why do you think that is?

Presumably because validating the other thousands of variants to the degree it
took to satisfy the FDA for the 3 variants they do look at would be extremely
expensive, and I suspect there may be other reasons as well (why would their
Illumina chips look for those variants in the first place given that they are
rare and they can't use them?). And knowing isn't that useful. DeCODE knows
the Icelanders with BRCAs, but isn't allowed to tell them:
[http://pulitzercenter.org/reporting/right-not-know-when-
igno...](http://pulitzercenter.org/reporting/right-not-know-when-ignorance-
bliss-deadly)

> Re the 'billions', which of the following is more likely:

You're backpeddling furiously. First it was '23andMe made billions' off poor
helpless customers, now it's merely they _might_ make billions. So now you're
damning them for doing what they haven't even done yet. Wow. It's not a
negative-sum game, you know.

~~~
Gatsky
You misunderstand my point.

Obviously, there are perfectly accurate and FDA approved tests for BRCA1 and
BRCA2. The point is 23andMe don't do these tests. Therefore, how can you argue
that their testing for lowly penetrant poorly characterised ultra-rare risk
loci (which means most of the positive tests will be errors, as in this case)
is somehow a great benefit to humanity, if they don't offer by far the most
common, clinically significant and life saving genetic test there is?

As I said, the answer is of course that 23andMe are acting in their own
interests. Anyone paying for the privilege to give away their genetic
information to a private company should realise this.

> why would their Illumina chips look for those variants in the first place
> given that they are rare and they can't use them?

And testing for ultra rare lowly penetrant AD loci is more useful?

Your entirely tangential example from DeCODE makes no sense. DeCODE was not a
user pays self-referred program. It was a research project.

If you read my original comment, I did not state in past tense that 23andMe
made billions (I presume you are merely careless in reproducing what I said,
rather than disingenuous). My comment specifically was 'Meanwhile 23andMe
makes billions selling the data to pharma?', indicating that there is
potential for them to make billions or that they are in the process, not yet
complete, of making billions. Their valuation by VC funding is entirely
supportive of that potential and process. The CEO has come out many times
stating their business plan is to sell population genetic data to pharma.

~~~
gwern
> Therefore, how can you argue that their testing for lowly penetrant poorly
> characterised ultra-rare risk loci (which means most of the positive tests
> will be errors, as in this case) is somehow a great benefit to humanity, if
> they don't offer by far the most common, clinically significant and life
> saving genetic test there is?

How can one thing be good if another thing is even gooder?

> As I said, the answer is of course that 23andMe are acting in their own
> interests. Anyone paying for the privilege to give away their genetic
> information to a private company should realise this.

It is not a negative-sum game. It is from the self-interest of the butcher we
are able to buy dinner, not his benevolent regard for humanity. 23andMe can do
a lot of good while seeking to do well.

> And testing for ultra rare lowly penetrant AD loci is more useful?

Apparently. Illumina and/or 23andMe chose to put it on the chip, so they
apparently felt it was worthwhile.

> Your entirely tangential example from DeCODE makes no sense. DeCODE was not
> a user pays self-referred program. It was a research project.

My point there was a comparison of the regulatory regimes that genetics
_companies_ (DeCODE is not a 'research project', is a former NASDAQ-traded
(DCGN)corporation which is now private post-bankruptcy, which did in fact use
'user pays self-referred programs' in addition to the national database they
were hired for) are under such that even when they know with high accuracy
about very serious mutations like BRCA, which you brought up as a huge
dereliction, they may still not be allowed to tell people, which illustrates
the incoherence and harm of the medical system in regards to genetic data;
given the question about whether they would even be allowed to tell people
(like you think they should not be allowed to tell people about AD loci), why
would they spend resources testing for it?

> My comment specifically was 'Meanwhile 23andMe makes billions selling the
> data to pharma?', indicating that there is potential for them to make
> billions or that they are in the process, not yet complete, of making
> billions

Oh, so the rest of that paragraph where you were contrasting how 'Meanwhile
23andme makes billions' to things that had already happened or were happening
were also just 'potential' too? I see. How very careless (not disingenuous) of
me.

~~~
Gatsky
> How can one thing be good if another thing is even gooder?

Why bother to be flippant this far down a thread on HN?

> It is not a negative-sum game.

I remain surprised that you should be quite so sanguine about the mutual
benefit of giving away data to tech companies. 23andMe and others recently
announced they would ask for explicit consent before sharing DNA information
with other parties. How a genomics company could go on for this long without
guaranteeing the privacy of its users is baffling.

> Apparently. Illumina and/or 23andMe chose to put it on the chip, so they
> apparently felt it was worthwhile.

'Worthwhile' and 'marketable' to a consumer audience are not equivalent, as I
have repeatedly pointed out with BRCA testing.

> My point there was a comparison of the regulatory regimes that genetics
> companies...

You referenced the sequencing of Icelanders, which was indeed a research
project (you've read the papers surely) and not a self-referred program,
regardless of what else DeCODE does or is. You can't make a point about
regulatory conditions in that setting and transfer it to consumer testing. But
are you trying to say that it isn't worth testing BRCA because DCT companies
might not be allowed to tell people the result, even though 23andMe are
currently offering BRCA results?

> Oh, so the rest of that paragraph...

I would suggest that your ongoing efforts to tell me what I meant in my
comment are better spent elsewhere. Particularly since as a privately held
company, we don't know 23andMe's revenue, what deals have been made or what
their future plans and projections are. What we do know is how much VC funding
they have received, and the return on investment that VC's expect.

------
vedtopkar
This is why the entire field of genetic counseling is a thing. Barring a few
specific diseases, genetic determinants of health are very complex and poorly
understood. Moreover, genetic testing, especially of the consumer sort, are
not always right. Even high-accuracy clinical tests have false
positives/negatives. You need more than a web portal to work through the
personal implications of genetic testing data as a patient.

------
faitswulff
Perhaps he simply has multiple genomes?
[https://www.nytimes.com/2013/09/17/science/dna-double-
take.h...](https://www.nytimes.com/2013/09/17/science/dna-double-
take.html?_r=0)

"But scientists are discovering that — to a surprising degree — we contain
genetic multitudes. Not long ago, researchers had thought it was rare for the
cells in a single healthy person to differ genetically in a significant way.
But scientists are finding that it’s quite common for an individual to have
multiple genomes. Some people, for example, have groups of cells with
mutations that are not found in the rest of the body. Some have genomes that
came from other people."

~~~
stochastic_monk
Last I heard, 23andme was using microarrays. The transition to massively
parallel sequencing didn’t go well and they rolled back.

The DNA placed on the chip will be a heterogeneous mixture of whatever kind of
cells provided. How they’d handle mosaicism, whether somatic or otherwise, I
don’t know.

------
nyolfen
perhaps it's de rigeur to mention this in a thread about genetic tests, but if
you've had it done already by one of the major providers, the service
mentioned in this piece (promethease) is really fantastic.

if you're lucky it won't tell you much you don't know, but learning about all
the possible things to look out for (heightened risk of diabetes and adverse
reactions to a medication, for me), sorted by magnitude, is exactly the kind
of thing you'd hope to learn from personal genotyping. it's much more granular
than what is offered by eg 23andme's health service, and is updated with new
research. it's more than worth the $5.

~~~
jstanley
How can we be certain that they aren't keeping a copy of our genome and/or
sending it to other people?

~~~
Avamander
Speaking of this issue, is there no FLOSS effort to create software that could
provide this analyzing service?

~~~
another-cuppa
Almost all the software used in biology is FLOSS. The problem is you need a
lab process to get the data in the first place.

~~~
Avamander
Say I have my genome in a text file, is there actually software that could
give me disease predisposition data?

------
Spooky23
IMO feeding the anxious with fear about supposed medical maladies is why their
practices are unethical.

~~~
jryan49
At least there are a million disclaimers, specifically saying if you have
depression or anxiety disorder or hypochondria to not enable the health
checks.

~~~
adventured
The concerning prospect, which seems inevitable, is that the government gets
heavily involved (after the nth scare story), regulates the hell out of the
sector, and then I'm paying $5,000 for a service that used to cost $99. That
is, after - if - I get permission and approval through my insurance provider,
and after I give a doctor $500 before and after each test. Then I'll be
reading articles about how expensive simple genetic services are in America
and nobody can figure out why. Then more laws will be proposed to fix the
problem, for something must be done about the gouging fees charged by genetic
services providers.

------
psychometry
This is why they need to report QC scores with each SNP's genotype. They
definitely have this data.

