$250 exome scan??

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Gilgamesh
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Re: $250 exome scan??

Postby Gilgamesh » Fri Dec 18, 2015 10:33 pm

J11, Thanks yet again for the update.

What is your recommendation to those of us interested in getting more SNPs sequenced? Wait a year or more, until another deal comes around, from a perhaps more reliable company?

Going with this 50X coverage deal seems like it might be a waste of time. For ex., I'd see a study linking a rare variant to tremendous protection, or risk, and I see that variannt in my results, but I'd end up wondering whether I really do have that variant....

G

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Re: $250 exome scan??

Postby J11 » Sat Dec 19, 2015 11:23 am

I'm voting with my wallet on this one.
$250 seems too good a deal to pass by.

This price point simply blows by all the other current deals.
I was quite surprised when they actually meant this seriously.
Some of it could simply be that BGI wants to protect its market dominance.

Everyone can see that genomics is going to be a huge huge industry of the 21st Century.
It is the sort of market that almost any nation presumably would want to be a part of:
high skill, high tech, envirofriendly ... . For whatever reason much of the industrialized world
is doing everything they can do outlaw it. This is giving BGI this enormous opening.
They probably figure that if they can simply dominate the market as the price moves down
they will wind up with a near long term monopoly for sequencing.

I have to admit that jumping onboard the sequencing bandwagon now simply might not be
the best strategy. Prices will tend lower over time: It would not be overly surprising to see
a $100 price point for a 50x exome a year from now (though as we have seen sometimes
a year or two can go by without a major reduction in prices).

I am starting to have the feeling that ultimately the price for genomes will be less than zero.
We have already received offers on 23andme to be paid $100 to speak to biotech companies, along
with hundreds of dollars worth of other goodies. The same probably could happen with sequencing.
Nanopores could move marginal cost near to zero. From there all sorts of interested parties including
insurance companies, government, employers among others might realize that preventing problems
would save them a ton of money. The negatively priced genome would quickly materialize.

The sequencing itself is not going to be overly informative until we have many many people
with their exome files. Some of the variants that were reported in our loved ones VCF file only occur
in 1 in 100,000 people. We would need population scale sequencing to have a sample for some
of these.

Those who really know what they are doing seem to stick with the inexpensive exome chips and
top it up with imputation. When I have asked some of these genomics companies about doing
the smart thing and doing some low cost gene chipping they were not very interested.

50x coverage would probably be fairly frustrating. Even our 65x exome has been quite frustrating.
65x coverage does not mean each base pair is sequenced 65 times. It means that if you take the
total base pairs sequenced divided by the length of the exome that you wind up with 65x average coverage.
The result is that there are quite a few segments that have 0x coverage and some with 400+x coverage.

The problem of the misreading of long stretches of consecutive nucleotides also persists. If you have about
20 consecutive Cs as occurs in the APP gene, you are probably going to wind up with a whole string of errors.
(This happened on our initial exome scan. Being told that you have a whole bunch of pathogenic variants with
high depth in your APP gene is not comforting, especially if you have a family history of Alzheimer's dementia.)

One thing that might help work around many of these problems is to take the 50x sequence and then impute
from there. Having such an extensive amount of sequencing would probably give you a very deep insight into
your genome.

With the 65x genome already done, and a 50x on top of that for our loved one, and a 50x exome for
an offspring we could have a very accurate look at our genomes. It will be especially interesting to see
if we could line up the toaster phasing by 10x Genomics. I have contacted them and asked if we could
send them a DNA sample so that they could add the index units unto the sample. This sample could then
be forwarded to BGI. This would be super awesome. We would then have the phasings of all of our variants.
When we contacted people on 23andme, we would then be able to tell them what variants from the exome
file they shared with our loved one.

It might not make sense for others to try exome sequencing at this time, though we are very excited to move
forward now.

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Re: $250 exome scan??

Postby J11 » Sat Dec 19, 2015 12:55 pm

It looks like someone just had an epiphany: This Alzheimer thing could go large.
http://www.alzforum.org/news/community- ... 60-percent

It could go very very large. The link talks about saving hundreds and hundreds of billions of dollars with
even a partially effective treatment. Congress has just stepped forward with $350 million in incremental
funding. Apparently someone has just realized that the massive wave of dementia is heading directly towards
us at high speed. It's "Batten down the hatches!" time ...finally.

I think if I were sitting in the big chair right now, I'd be thinking of doing some sort of Alzheimer Exome Project.
It would make a whole bunch of sense to me. The genetics of Familial Alzheimer's is nearly a complete mystery.
Finally determining what specific variants and pathways lead to dementia could be overwhelmingly helpful.

Item number one would probably be to sequence the entire early onset population of Colombia.
Doing some large scale exome/genome sequencing in the States would also be high on the
list. An Alzheimer Genetics Project with a budget of $25 million might finally unlock the
biology behind dementia. At some point they would be able to make an inexpensive dementia
gene chip that could provide comprehensive coverage of the risk and protective variants.

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Re: $250 exome scan??

Postby J11 » Sat Dec 19, 2015 8:32 pm

It would be just amazing if exomes scans were able to find variants that could actually be treated with
existing therapies. This seems at least plausible.
For example, there are known issues in metal genes etc. .

If such variants could be found, then a near immediate and eternal payback would result.
Such people would likely avoid dementing illness and would become net contributors to the nation's finances.

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Re: $250 exome scan??

Postby Gilgamesh » Sun Dec 20, 2015 2:04 am

Yes, the price ultimately could well be less than zero. Thinking of Jaron Lanier's thoughts about how we all work for Facebook and the like for free. We are unpaid laborers, aside from the "payment" which is the right to use the social media. Those who fill out surveys at 23andMe are doing the same thing: working for free, to help 23andMe get huge contracts with Big Pharma. $99? $199? They should pay us, or, at least, it should be free (maybe under the condition that one fill out surveys).

About BGI: Let us know how it goes. I'm on the fence still.

Anyone other than J11 and me thinking about this?

G

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Re: $250 exome scan??

Postby J11 » Sun Dec 20, 2015 1:38 pm

I was trying to figure out how they could spend that 350 mill sensibly - all together about a b note. ? Generally when you start talking large scale government projects it really isn't about spending hard earned money from tax payers wisely. I thought they might start the Alzheimer spending spree by buying a forest of potted trees. Sequencing a few hundred thousand exomes would not be much better value for the money.

Then I thought why not try an extended family tree project? Something like what I am trying? That could make a whole lot of sense. If you go back five to seven generations and then trace forward there would be a truly enormous number of descendants.
So in the US you have 300 million people, take the 20 per cent with earliest dementia onset, remove the 50 per cent epsilon 4 and you are left with 30 million, divide them into 30,000 extended families of roughly 1,000 each, in each of these extended families do an exome scan of someone with dementia and gene chip others with dementia in this extended family to narrow the risk segment down.

This would make so much sense. An organized effort at the national level to find the causative variants for dementia in the community is money wisely spent. The payoff would simply be massive. Once people without an APOE e4 knew what variant was causing the dementia in their family they could take advantage of existing reproductive technologies to stop transmission to another generation. Eventually the cost savings from a dementia free community would exceed a trillion dollars annually in the US.

Privacy concerns could largely be addressed as all that might need to be disclosed is whatever variant was found. Such an organized effort would avoid much duplicated work by people researching their own individual trees.

This idea makes so much sense. For a modest investment there would be a truly massive payback. The potted plants can wait.

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Re: $250 exome scan??

Postby Gilgamesh » Wed Dec 23, 2015 6:03 am

Gilgamesh wrote:Anyone other than J11 and me thinking about this?
No responses yet. So no one else is considering this? That surprises me.

I've been curious about how easy Survey Monkey is to use. Partly to find out, partly to find out why people aren't expressing more interest in the BGI offer, I created a survey. Would folks mind cruising over to

https://www.surveymonkey.com/r/9DWMR8P

and answering 8 simple questions?

(The survey is called "Market Research Template" or smth similar. Forgot to rename the template! But it's from me, and is not market research!)

It's not greatly designed. Partly I just wanted to test out Survey Monkey. But it will give us/me an idea about more people aren't jumping on this chheap sequencing offer.

Thanks!
G

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Re: $250 exome scan??

Postby SusanJ » Wed Dec 23, 2015 2:00 pm

To stir more discussion, I want to post my answer.

It seems you have to spend a lot of time teasing out information. And, I'm not convinced that the extra information is actionable in any way. In other words, I'm not sure it would change what I'm doing today.

If I'm missing something in what I'd gain with the extra info, then please let me know.

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Re: $250 exome scan??

Postby Stavia » Wed Dec 23, 2015 4:54 pm

I'm with Susan. I'd rather spend my time currently living life than trawling though the data. And anything I learn I do not believe will change my interventions.

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Re: $250 exome scan??

Postby jenniferthequeen » Wed Dec 23, 2015 9:29 pm

I have to agree with Susan and Stavia.

While the idea of getting more information is compelling, and the idea of getting bargain pricing doubly so, without a clear means with which to use the data I feel my money is better spent in the organic produce aisle or by upgrading to a better Vitamix.

My dream would be sequencing combined with a post analysis and a personalized Idiot's Guide to 4/4 Management.

I don't weigh in often, but I must say you are a great bunch. Thank you for being out there ferreting through the gobs of ever changing information for the 4/4 community and for providing a confidential, credible, public resource for us. - JQ


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