Genomics. Personalized medicine. Math.

[retina]

Originally Posted by LaurV

... we have nothing to hide...

I personally have lots to hide. And I bet you do to. The rhetoric of "nothing to hide" is the real propaganda here IMO.

Sometimes people don't want to be found (for perfectly innocent reasons like adoption cases and sperm donations) and it is terrible to think that they could be identified against their will when they have done nothing wrong.

So yeah, everyone has things to hide. No one has a 100% open life. If someone says they do then just ask them for their banking username and password, or who they secretly have a crush on.

[LaurV]

That was somehow sarcastic... hehe, that is why the smiley.
On the other hand, I can post my username and password for the bank account, and if you find any money there, we share it

[Till]

1. Genome sequencing:

Let your genome getting sequenced seems quite ambivalent to me:
Some people might profit from it directly but most not. All data will be stored somewhere for their lifetime and longer. That's part of the business model. Insurance and other companies may get access to that data in the future, I fear.



2. Gene editing:

On Crispr there has been a pretty interesting debate lately. Companies tried to sell the latest generation as something like breeding, and that organisms modified by it should not fall into the category of "genetically modified organisms" (GMOs). Here is some account of it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302053/

[ewmayer]

5-HTTLPR: A Pointed Review | Slate Star Codex

If 5-HTTLPR plays such an important role in depression, might it also have relevance for antidepressant treatment? A few studies of specific antidepressants started suggesting the answer was yes ... Does this mean psychiatrists should be testing for 5-HTTLPR before treating patients? A cost-effectiveness analysis says it does. There’s only one problem.

ALL. OF. THIS. IS. LIES.

Or at least this is the conclusion I draw from Border et al’s "No Support For Historical Candidate Gene Or Candidate Gene-by-Interaction Hypotheses For Major Depression Across Multiple Large Samples", in last month’s American Journal Of Psychiatry.

They don’t ignore the evidence I mention above. In fact, they count just how much evidence there is, and find 450 studies on 5-HTTLPR before theirs, most of which were positive. But they point out that this doesn’t make sense given our modern understanding of genetics. Outside a few cases like cystic fibrosis, most important traits are massively polygenic or even omnigenic; no one gene should be able to have measurable effects. So maybe this deserves a second look.

While psychiatrists have been playing around with samples of a few hundred people (the initial study “discovering” 5-HTTLPR used n = 1024), geneticists have been building up the infrastructure to analyze samples of hundreds of thousands of people using standardized techniques. Border et al focus this infrastructure on 5-HTTLPR and its fellow depression genes, scanning a sample of 600,000+ people and using techniques twenty years more advanced than most of the studies above had access to. They claim to be able to simultaneously test almost every hypothesis ever made about 5-HTTLPR, including “main effects of polymorphisms and genes, interaction effects on both the additive and multiplicative scales and, in G3E analyses, considering multiple indices of environmental exposure (e.g., traumatic events in childhood or adulthood)”. What they find is…nothing. Neither 5-HTTLPR nor any of seventeen other comparable “depression genes” had any effect on depression.

I love this paper because it is ruthless. The authors know exactly what they are doing, and they are clearly enjoying every second of it. They explain that given what we now know about polygenicity, the highest-effect-size depression genes require samples of about 34,000 people to detect, and so any study with fewer than 34,000 people that says anything about specific genes is almost definitely a false positive; they go on to show that the median sample size for previous studies in this area was 345. They show off the power of their methodology by demonstrating that negative life events cause depression at p = 10^-144, because it’s pretty easy to get a low p-value in a sample of 600,000 people if an effect is real. In contrast, the gene-interaction effect of 5-HTTLPR has a p-value of .919, and the main effect from the gene itself doesn’t even consistently point in the right direction. Using what they call “exceedingly liberal significance thresholds” which are 10,000 times easier to meet than the usual standards in genetics, they are unable to find any effect. This isn’t a research paper. This is a massacre.
…
what bothers me isn’t just that people said 5-HTTLPR mattered and it didn’t. It’s that we built whole imaginary edifices, whole castles in the air on top of this idea of 5-HTTLPR mattering. We “figured out” how 5-HTTLPR exerted its effects, what parts of the brain it was active in, what sorts of things it interacted with, how its effects were enhanced or suppressed by the effects of other imaginary depression genes. This isn’t just an explorer coming back from the Orient and claiming there are unicorns there. It’s the explorer describing the life cycle of unicorns, what unicorns eat, all the different subspecies of unicorn, which cuts of unicorn meat are tastiest, and a blow-by-blow account of a wrestling match between unicorns and Bigfoot.

This is why I start worrying when people talk about how maybe the replication crisis is overblown because sometimes experiments will go differently in different contexts. The problem isn’t just that sometimes an effect exists in a cold room but not in a hot room. The problem is more like “you can get an entire field with hundreds of studies analyzing the behavior of something that doesn’t exist”. There is no amount of context-sensitivity that can help this.

Second, most studies about 5-HTTLPR served to reinforce all of our earlier preconceptions. Start with the elephant in the room: 5-HTTLPR is a serotonin transporter gene. SSRIs act on the serotonin transporter. If 5-HTTLPR played an important role in depression, we were right to focus on serotonin and extra-right to prescribe SSRIs; in fact, you could think of SSRIs as directly countering a genetic deficiency in depressed people. I don’t have any evidence that the pharmaceutical industry funded 5-HTTLPR studies or pushed 5-HTTLPR. As far as I can tell, they just created a general buzz of excitement around the serotonin transporter, scientists looked there, and then – since crappy science will find whatever it’s looking for – it was appropriately discovered that yes, changes in the serotonin transporter gene caused depression.

But this was just the worst example of a general tendency. Lots of people were already investigating the role of the HPA axis in depression – so lo and behold, it was discovered that 5-HTTLPR affected the HPA axis. Other groups were already investigating the role of BDNF in depression – so lo and behold, it was discovered that 5-HTTLPR affected BDNF. Lots of people already thought bad parenting caused depression – so lo and behold, it was discovered that 5-HTTLPR modulated the effects of bad parenting. Once 5-HTTLPR became a buzzword, everyone who thought anything at all went off and did a study showing that 5-HTTLPR played a role in whatever they had been studying before.

From the outside, this looked like people confirming they had been on the right track. If you previously doubted that bad parenting played a role in depression, now you could open up a journal and discover that the gene for depression interacts with bad parenting! If you’d previously doubted there was a role for the amygdala, you could open up a journal and find that the gene for depression affects amygdala function. Everything people wanted to believe anyway got a new veneer of scientific credibility, and it was all fake.

Third, antidepressant pharmacogenomic testing.

This is the thing where your psychiatrist orders a genetic test that tells her which antidepressant is right for you. Everyone keeps talking these up as the future of psychiatry, saying how it’s so cool how now we have true personalized medicine, how it’s an outrage that insurance companies won’t cover them, &c. The tests have made their way into hospitals, into psychiatry residency programs, and various high-priced concierge medical systems. A company that makes them recently sold for $410 million, and the industry as a whole may be valued in the billions of dollars; the tests themselves cost as much as $2000 per person, most of which depressed patients have to pay out of pocket. I keep trying to tell people these tests don’t work, but this hasn’t affected their popularity.

A lot of these tests rely on 5-HTTLPR. GeneSight, one of the most popular, uses seven genes. One is SLC6A4, the gene containing 5-HTTLPR as a subregion. Another is HTR2A, which Border et al debunked in the same study as 5-HTTLPR. The studies above do not directly prove that these genes don’t affect antidepressant response. But since the only reason we thought that they might was because of evidence they affected depression, and now it seems they don’t affect depression, it’s less likely that they affect antidepressant response too.

The other five are liver enzymes. I am not an expert on the liver and I can’t say for sure that you can’t use a few genes to test liver enzymes’ metabolism of antidepressants. But people who are experts in the liver tell me you can’t. And given that GeneSight has already used two genes that we know don’t work, why should we trust that they did any better a job with the liver than they did with the brain?

Remember, GeneSight and their competitors refuse to release the proprietary algorithms they use to make predictions. They refuse to let any independent researchers study whether their technique works. They dismiss all the independent scientists saying that their claims are impossible by arguing that they’re light-years ahead of mainstream science and can do things that nobody else can. If you believed them before, you should be more cautious now. They are not light-years ahead of mainstream science. They took some genes that mainstream science had made a fuss over and claimed they could use them to predict depression. Now we think they were wrong about those. What are the chances they’re right about the others?

Yes, GeneSight has ten or twenty studies proving that their methods work. Those were all done by scientists working for GeneSight. Remember, if you have bad science you can prove whatever you want. What does GeneSight want? Is it possible they want their product to work and make them $410 million? This sounds like the kind of thing that companies sometimes want, I dunno.

…I think we should take a second to remember that yes, this is really bad. That this is a rare case where methodological improvements allowed a conclusive test of a popular hypothesis, and it failed badly. How many other cases like this are there, where there’s no geneticist with a 600,000 person sample size to check if it’s true or not? How many of our scientific edifices are built on air? How many useless products are out there under the guise of good science?

[masser]

Originally Posted by ewmayer

…I think we should take a second to remember that yes, this is really bad. That this is a rare case where methodological improvements allowed a conclusive test of a popular hypothesis, and it failed badly. How many other cases like this are there, where there’s no geneticist with a 600,000 person sample size to check if it’s true or not? How many of our scientific edifices are built on air? How many useless products are out there under the guise of good science?

idk, this sounds pretty good to me. imo, we need more mythbusting studies like this.

[Batalov]

Everything you wanted to know about real sequencing^TM and genotyping (23 and me and similar).

Well done, Destin! Saved me so much typing...

[S485122]

The privacy concerns are once again paramount and are not fully addressed in this commercial. The scheme explained in the video has similarities with the provision envisaged to secure the secret of vote when The Netherlands were planning to test Internet voting : a third party would check the votes were cast by people having a right of vote (thus knowing what each individual voter had chosen) and would have the obligation in their contract to destroy the data after the whole voting process was concluded. Such a thing is of course a joke : digital data is easy to loose, but it is also impossible to have the proof that it has been destroyed and that there are no copies remaining somewhere. The scheme was abandoned.

The genome and the genotype is highly private data, with whom is it shared, to whom is it sold ? law enforcement, pharmaceutical companies, insurance companies, genealogists, family, other interested people ... whomever has the money ?

For instance there is a new trend, people trying to do genome based genealogy, which leads to revelations of old events without the explicit consent of all involved : even people who did not submit their sample are involved. It could lead to funny situations in matters of inheritance though, generating a lot of money for lawyers and solicitors.

As a mitigating factor, the hype around 23 and me and those other companies lead some people to submit samples to different companies and compare the results. It was not very reassuring about the quality of the conclusions and the genotyping itself. But this brings us to another type of litigation.

Jacob

[kladner]

I have encountered something which I perceived as using DNA testing as a profit center with limited medical benefits. I have been diagnosed with "low grade" (technical term) prostate cancer (Gleason 3 + 3 for those in the know.) I have had 2 biopsies collected. The urology practice pitches genetic identification as a means of insuring the identity of the specimens. I was also told that it yielded some useful information about the cancer cells themselves. On the first biopsy I agreed to this, and it ended up costing me an additional 300 USD out of pocket. I declined this service on the second biopsy.

However, the profit center aspect was clearly shown. I noticed that all the specimen containers came in a kit which was prominently labeled with the name of the genetics testing firm. It made me wonder about kickback relationships between doctors and labs.

I considered posting in "Happy Me" about my happiness that the recent biopsy continued on the "low grade" course, but held back because of the sensitive nature of the topic. I have found that mentioning my condition makes some people (males) cringe. This thread gave a me a good context for saying something.

Specifically, only one of twelve samples taken had any abnormal tissue, which was still 3 + 3 low grade, and that tissue was only about 10% of that specimen. Mind you, the doctor said that "luck of the draw" plays a role here, as in, "did the needle happen to hit an affected spot in the gland?" He said that at this level the biopsy might have come up completely clean, even if abnormal cells are known to exist.

Part of my encouragement comes from the fact that it took (many) years of being told that my benign prostatic hyperplasia (BPH) might not be totally benign, and that I should consult a urologist, before I bit the bullet. The fact that the cancer had not run wild in those years gives me hope that it may continues in its relatively non-aggressive mode.

[Batalov]

I agree that Destin's video takes a cavalier approach to privacy -- "it is only 0.2% of your DNA, problem solved!"

Did you know that data about just 24 positions on your genome uniquely identifies you *? This is called CODIS and is widely used not only by FBI and law enforcement (and internationally unified and used in 50 countries) but also by the paternity tests that you can buy in nearly every pharmacy. The cost of this identity check in volume is very low - $20-30 per sample (so for paternity, 3x that). This is because these positions are multialleleic - each can report to which of the 10-20 allelotypes you belong, so << 1 / 10^24 is the probability of error.

For SNPs, there is almost always just two allelic states (three haplotypes, e.g. AA, AC, CC) - so you need perhaps several hundred and you will have uniquely identified an individual. 23 and me uses ~600,000.
______________

* There is only one exception - identical twins.

[Batalov]

A wonderful (and free!) learning opportunity -

April 9-11, 2021 Livestream hosted by Mayo Clinic, Rochester, MN
Undiagnosed Diseases Network International (UDNI) CONFERENCE & MAYO CLINIC SCIENCE SESSION

Join us to learn more about alternative omics diagnostics, genome engineering, therapeutics, novel funding models and emerging science in rare and undiagnosed diseases.

This broadcast aims to continue an international collaborative effort involving rare and undiagnosed diseases organizations throughout the world. Attendees work together to facilitate data sharing and discuss recently diagnosed and undiagnosed cases evaluated by Undiagnosed Diseases Network International (UDNI) members and participants.

[jwaltos]

Originally Posted by Batalov

.. and we have shockingly nothing about genomics at this forum. I volunteer to answer any questions that might be of interest...

First, thank you for providing a knowledge gateway to this multi-faceted field as a
working professional. I wasn't aware this thread existed until today due to your post.

Some of my lay background:

A bit of history where I knew the victim's sister while I was at UBC,
https://www.100milefreepress.net/new...l-teens-death/

There was a documentary I watched about a year ago regarding Dr. Jeffreys who initiated the field of DNA identification. I'd be interested in learning more about how this happened, separating fact from fiction.

Scientific American published an article about a researcher who developed an RNA factory that industrialized the process of RNA replication. The article may have been in the mid-90's and the fellow had blonde hair and circular glasses. I haven't been able to find the article but how far has this field advanced and why? Where are the brilliant minds that are the trail-blazers..public..private or secret?

I've researched articles, patents..etc.. on exotic forms of calculation such as phase changes and DNA computation. My formal learning regarding biology topped out in high school but I've read and learned much more on my own.

Some questions:

Is the study of genomics primarily within the realm of biology affiliated with chemistry..etc..or is there a different and unique characterization of such studies that straddles the life sciences and things non-living?

Are A,C,T,G and U the only nucleotides? Is there any correlation with this encoding and the Base 10 number system? I've seen questionable works on this but is there anything of substance?

Is there an underlying structure that is sub-atomic in nature that provides the "encoding" for the genetic process? That is, is there a precursor "code" to the genetic code? If there is, is there an antecedent to the sub-atomic structure?

I posted something in my blog area (since effaced) regarding a possible goal oriented process of genetic evolution..do you have any opinions or pointers on this?

In my virtual library I have numerous texts on many topics including bio-informatics. Which text within this field best exemplifies creativity and imagination rooted in fact? One possible tendril in this regard is AI married with Quantum computation.

Why are you interested in computing large primes and how does integer factorization factor into this (pun intended).

Regarding solutions/answers to any questions of import, the answers are ancillary to the conceptual foundations that are the well-spring for those answers. What genre(s) of mathematics are capable of expressing most comprehensively what is to be known about genomics and does such a toolkit presently exist? An irony is the fact that we are built from these little bits and we (all these concerted little bits) are trying to figure out how it happened.

Finally, what must I learn AND understand to ask better questions?