Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in ME/CFS: A Pilot Study. Perez et al 2019

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Yes, the SNPs that are present in only one version or the other should have been segregated and analyzed separately.
This was not done in this study. For 525 rsID's I multiplied the MECFS frequency by 383, the number of participants, and the answer for all of them was a round whole number. This should not be the case with mixed v4 and v5 data.
 

nandixon

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Okay, good to know they did one thing right anyway. When I saw the patient frequency for the one IDO2 SNP (rs4736794), which is only found on 23andMe v4, so low at only 1% versus the expected 13% (in Supplementary Table 1), I thought they might not have correctly split things. So I guess perhaps the sample size of v4 patients was just too small.(?)
 
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I don't know what to make of this anymore. v4 data has changed over time as 23andme has cleaned up the files and also added new data.
https://you.23andme.com/tools/data/download/
Quality
The rapid advance of genotyping technology means that our ability to interpret your raw chip data will improve over time, and thus the version of your genome residing on our servers will improve in both completeness and accuracy. For that reason, customers who want the best available data should occasionally check back and update their downloaded files.
Change Log
July 27, 2017 As part of our continuous efforts to improve the quality of data present in your raw data download, the number of SNPs available in your download may have changed.
July 22, 2015 We updated call filtering in the downloaded file so it matches filtering in the Raw Data tool. Some customers may see "--" (a "no call") as their genotype for some SNPs on the X chromosome, Y chromosome, or in their MT DNA, where their downloaded data file previously showed a "D" call.
July 28, 2014 Analysis of our data has allowed us to improve the interpretation of over 10,000 SNPs genome-wide on the V4 chip. In the next couple of days, V4 customers will see calls for SNPs that previously did not appear in their raw data.
So it's possible that some items that appear in one v4 file might not appear in another v4 file. It's a mess. Only values that appeared in all files should have been compared.
 
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I just downloaded a new version of my v5 23andMe raw data file. There are quite a few additions and deletions to the data.......... For example, three MT variations that I had have been cleaned up and I no longer have them.
 
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Sidereal

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I'd previously been a fan of hers, in particular with respect to her homeostasis theory for Gulf War Illness and ME/CFS, but now I'm not sure that I can trust anything coming out of her group.

Honestly, it makes me think that she doesn't really care about actually finding the underlying cause of ME/CFS.
I've never trusted a single thing that came out of her group. In every media appearance she is still going on about NK cells, a spurious finding from 30 years ago, even though this result has repeatedly failed replication attempts in multiple labs.

I don't even read her papers anymore because I know what I'll get, although the things you've discovered here are completely shocking. Sadly, this kind of thing is commonplace in science now with the widespread availability of open access pay-to-publish predatory journals.
 

kday

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I can confirm that 23andMe's data is a mess. There's also many variations of v4 and a couple variations of the custom v5 GSA chip.

23andMe is anything but transparent about their data. And the "raw" data can be altered, which can make it extremely hard to work with.

AncestryDNA doesn't have nearly as many issues with their raw data. The data scientists at 23andMe were anything but careful when customizing their data and applying their proprietary identifiers. They should have left the data science up to Illumina.
 

kday

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WGS data from many different companies is so much easier to handle than 23andMe data. Looking forward to the day when a WGS company knocks them down. I have a feeling that that company may end up being Nebula Genomics. But it may be a number of years until such a platform is widely adopted.
 

kday

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There is useful things in that study if you can filter the signal from the noise. For example, this supports previous research about a 2.5 times times increased frequency of Mannose-Binding Lectin Deficiency in ME/CFS.

I believe the data is pretty consistent across platforms for certain MBL2 SNPs.

Mannose-Binding Lectin Deficiency is the most common immune deficiency worldwide with a prevalence of about 5 to 10%.
https://ghr.nlm.nih.gov/condition/mannose-binding-lectin-deficiency#statistics

But it's so common, that almost nobody knows about it and is treated as it it were an orphan disease. It's a lot more common in certain parts of Africa and has a lot to do with the with the immune response to and severity of Malaria in that region. Common and deleterious.

And it's a risk factor for ME/CFS. I'm sure treatments could be made for it (and I have my own hypotheses for what these treatements might be), but nobody cares.
 

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Jenny

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Hi kday
What treatments do you think would help mannose binding lectin deficiency? I have this - in fact I have no MBL at all. But I don’t seem to get any more infections than normal people.

I wonder if some people with ME have MBL deficiency together with some other genetic variations, the result of which is to constantly ramp up the immune system to deal with the threat of infections. And it’s the ramped up immune system that causes our symptoms.
 

kday

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Hi kday
What treatments do you think would help mannose binding lectin deficiency? I have this - in fact I have no MBL at all. But I don’t seem to get any more infections than normal people.

I wonder if some people with ME have MBL deficiency together with some other genetic variations, the result of which is to constantly ramp up the immune system to deal with the threat of infections. And it’s the ramped up immune system that causes our symptoms.
It can't be proven without real research, but I hypothesize that the Cusack Protocol may be addressing the Lectin pathway in a very powerful way.

And if you were try it, I hypothesize that you may end up feeling quite ill at first as substrates will initially ramp up immune response.
 

kday

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I don't think our immune response is ramped up necessarily. I think non-lectin immune pathways may just have to overcompensate for the lack of mannose-binding lectin (MBL) function.

Though mannose-binding Lectin is just a risk factor. So not everyone with ME/CFS will have such deficits.

Throw in ME/CFS and low NK Cell Function with lack of MBL, and no wonder some of us are exploding mast cells!
 
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The data errors are so atrocious that they're indicating that Klimas never even bothered to look at any of the data. (I'm making an assumption here that someone at her level couldn't possibly be so ignorant in their understanding.)

I'd previously been a fan of hers, in particular with respect to her homeostasis theory for Gulf War Illness and ME/CFS, but now I'm not sure that I can trust anything coming out of her group.
Very disappointing.. she has said in the past that she is obv not a systems engineer, but that she works closely with them. She always refers to the genetics team and their use of a super computer to crunch numbers in a that-thing-that-the-kids-on-the-team-do sort of a way.

I also have noticed that she has said repeatedly “we’re starting the trial next month”, for more than a year period, about the women’s post menopausal trial, but, did it ever start? She also had said “and then soon after we’ll start the men’s trial”, but again, did it ever get going? That had made me hesitant to donate to them.
 
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nyanko_the_sane

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Yes, very sad the results of the study were botched on several levels. But just for fun, I cleaned up the supplemental cohort data a bit. I ran a query on it against my 23andMe data and it returned 191 matching markers out of the 573 in my revised set. How many matches have any of you found on your data?
 

nyanko_the_sane

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If you query a database and order by CADD score and run this through another database, you get something that looks like a creature with a immune system, nervous sysytem, collagen, brain, bone structure, etc. You get something that closely resembles a mammal pr primate. I only know because I've done it before.
Yes, you might have stumbled across the missing link by approximation. Just being silly.
 

vision blue

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The very first SNP in a table on that study (GPBAR1 rs199986029) has a global allele frequency of 0.000004081 in gnomAD. Literally only 1 out of 245,032 didn't match reference. 1 heterozygote worldwide in this database.

https://gnomad.broadinstitute.org/variant/2-219128356-G-C

If you combine the other frequency databases, up to 4 in the world have it. But the same people can be in different databases. So it's probably 2 people total.

This was literally one of the first things I examined in the study. I kept looking to see if I typed the rsID wrong.
I agree with you completely and had noticed this. With only 3 people worldwide having this variant, it clearly is not the case that 70 percent of those with CFS have it.... My guess is that this is a bad call on the part of 23andme. This happens occasionally with 23and me data. another example is another actually from their list of differences CYP2D6. For a long time, 23andme mistakenly showed many people had a variant here that in fact they do not. NOt sure if it has been corrected yet, but likely many of those participants data got included in the study.

The question becomes why on earth wasn't this error with GPBAR1 caught? Instead they go on to intepret it as if it were a real effect! I mean, if it was a real effect, then you've got a smoking gun here and THE cause for CFS! NOte that all their subjects come from 23andme, but their controls come from already published normal reference stas like 1000 geneome project. Since 23andme makes plenty of mistakes, one really needs the control data to come from 23andme as well. That should not be hard to do.

And even if they were going to use the published normative data, still, someone should catch errors like this.

i just saw another poster said they had undergrads analysizng the data. that makes sense and it must be something like that. I'm often generally suspcious of papers with many authors, even when there areen't undergrads involved.

alas, means pretty much one needs to discount everything that is said. the oly way to rescue is if someone were to take those 50 ssnps and check frequenies agains non CFS folk - but only those tested on 23andme (and with the same chips).

one can howerver take note of the software they used and generally repeat properly.

I recently started reading klimas' papers and finding them very uneven. Iread one that was terrfic on antibodies to a protein compenent of herpes viruses in those with cfs and gulf war syndrom, so eagerly started wroking my way through papers- only to find they vary so much in quality i might as well be choosing articles at random, so wil stop my efforts of reading thru papers with her name on the authrorship. myabe will look for any with her name as first or last author.

sorry for this long post. Just wasted my time looking at their genetic data. i wil spend just a tiny bit more and see if there's anything i can mine from their supplementary table, if they have some raw datra.

oh, one more thing- the CAMM score is just silly. they use that as the primary metric of whether something is likely to be deletrous- anything above 20 - nonsense, that's pretty close to the mean CAMM score of loads of on-offs.
 
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i wil spend just a tiny bit more and see if there's anything i can mine from their supplementary table, if they have some raw datra.
I did that and it was a waste of time. The study only looked at v4 and v5 data 23andMe data. I looked at 525 entries in that table. In my 23andMe v4 data I only had genotype info for 190 of them. So that tells you straight away it's a complete and utter cock-up. However I was appreciative of the fact that they included all that supplementary data for people to look at.

I wrote to Travis Craddock detailing the many issues, and did not get a reply. I and others contacted INIM on Twitter and Facebook to highlight the errors, and no-one got a response.
I recently started reading klimas' papers and finding them very uneven. I
I was also excited to read the latest modelling study. Turns out they didn't measure a lot of the parameters used in the model, such as hormones. The first paper they wrote generated the model. The next paper improved it on another set of data. They NEVER ran a validation of the model after tweaking on a separate set of data. Basic mistakes. Very disappointing.
 

vision blue

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Yup, theyll have to start from scratch. I wonder if the 3 snps that "survived" the scrutiny of the re=analysis will surface again as risks for CFS when the study is done again properly. What a shame (on so many levels). Still trying to decide if i should resign from the Klimas fan club. Perhaps i can allow her one mistake? i'm always leery of multiauthor papers. there's often no accountability as each person shaves off one piece of the project and there's no gatekeeper.