Machine Learning-assisted Research on ME/CFS

@Perrier @ScottTriGuy @Andy


After having received a full genome from a severely ill patient ,i analysed the patient's DNA file through a DNA Analysis service. Some things i found that could be of interest :





1) We note , peroxisome biogenesis disorder



Then found the folllowing SNPs on VKORC1, related to warfarin and Vitamin K metabolism :






@wigglethemouse even though these appear to be fairly common, could being homozygous on all of these bring on problems?

2) We note VKORC1 which is related to Vitamin K metabolism.


Post in 2017, observe Peroxisome, Vitamin K, VKORC1 below :

https://forums.phoenixrising.me/threads/machine-learning-assisted-research-on-cfs.51283/#post-846815

 

Generally this is all too technical for me but I'll note that I had numerous blood-thining injections while I was in hospital recently (I don't know if they were warfarin or not).

 

cc : @Perrier

Thank you @Andy.

FWIW, this is a slide from my presentation at euromene which contains a snapshot from a comment at SolveCFS. Observe also the comment from the doctor saying that this looks like Post-viral fatigue :

 

Ahh, I see. I'm doing much better after my surgery which would suggest that I don't have that problem.

 

I guess it could - the more you have on the same gene the more likely that there will be an effect - warfarin dosage if used may need to be adjusted per the picture you posted. With that in mind it wouldn't harm for this person to get a clotting test done too to get some real data on the effect KORC1 is having right now.

Here is the clinical relevance per Wikipedia if you haven't seen it. I'm sure you read the clinvar reports for the 3 variants as well.
https://en.wikipedia.org/wiki/VKORC1#Clinical_relevance

EDIT : As an aside some doctors are testing clotting in ME-like patients for antiphospholipid syndrome and Lupus Anticoagulant. I saw this on a talk by Jill Schofield in Denver (non-ME talk) who specialises in chronic complex diseases that other doctors find hard to diagnose.

 

@mariovitali have you any idea why Melatonin is up near the top in your recent analysis? I haven't seen much data about Melatonin levels and ME.

It's not the sort of thing the doctor tests for, and I don't see Melatonin or precursors listed in the Hanson metabolomics dataset that was published last year to investigate more. Some patients do take it as a supplement though.

 

I have no idea why this is so. For quite some time the system would output things and ever since i was trying to understand why this was so. Vagus nerve was there for quite some time. Acetylcholine even earlier :

https://forums.phoenixrising.me/thr...e-treatment-for-cfs.37244/page-65#post-679562

But what i can do is use the system to identify what associates with Melatonin :



My hypothesis is that it is related to oxidative stress control. I have no idea what the system finds regarding association of melatonin and indoleamine or hypothalamus inflammation but there must be some connection.

 

It seems melatonin is an indoleamine according to this
https://en.wikipedia.org/wiki/Indolamines

It seems the hypothalmus controls melatonin circadian rhythm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001216/

Interesting to ponder about Melatonin being an anti-inflammatory for the central nervous system ......... I wonder how important that role is.

Thanks for sharing your analysis.

 

I had a closer look @wigglethemouse to try to understand more. There seems to be a connection with POMC (Propiomelanocortin) but i have to dig deeper to this.

 

Here is the latest update. Before continuing, i must say that i am very excited about the latest post.

It appears -based on the methodology that i use- that the brainstem and vagus nerve are highly relevant to the symptoms of ME/CFS. I linked the new post from my blog on Twitter and got this tweet from a Researcher at the Karolinska Institutet :




The post can be found here :


http://algogenomics.blogspot.com/2019/06/parasympathetic-nervous-system.html

Some key points :

1) The vagus nerve and any brainstem abnormalities should be further investigated
2) The vagus nerve is responsible for proper liver function, gallbladder function and -more importantly- a proper inflammatory response.
3) The amelioration of symptoms through the activation of parasympathetic nervous system should be furter investigated. Vagal stimulation can be used to achieve this.
4) The cholinergic anti-inflammatory pathway should be further investigated.


I also have a very important call tomorrow with a well known ME Research organisation. Things are finally moving

 

Great news @mariovitali

 

If melatonin is being prioritised as an antioxidant would yhis knock on to body clock dysregulation and sleep isdues?

 

@Amw66 i am not sure yet if this is the case but i am working on it.


I got a reply from Janet Dafoe saying that she forwarded my post to Ron. I added one more post which proposes a pharmacological target and i tagged @JenB, Van Elzakker and Petter Brodin :




Let's hope this sheds some light.



Link : https://bit.ly/2EZG4sw

 

@Amw66

I think @wigglethemouse got it right. Indoleamine comes from melatonin. Melatonin inhibits NMDA (recall the post i linked above, talks about NMDA inhibition). I believe this is the connection.


An example :

 

I had no idea this PDF existed. Talks about the Vagus nerve, the Sympathetic System (SNS) and Parasympathetic system (PNS). Spot on and it is from the ME Association.

https://www.meassociation.org.uk/wp...eview-Dysfunctional-ANS-in-MECFS-24.01.18.pdf

Regarding the attempts to increase the vagal tone -and as a result the PNS- i can say that i tried dunking my head in ice water and saw immediately vast improvements after a major crash i had because of a medication i got.

I was not able to eat, had loss of appetite and had some fatigue. I could barely drink water. Seeing what happened with Jen Brea and looking at the algorithmic output suggesting the vagus nerve, I decided to increase my vagal tone by using this trick so i got a large bowl, filled it up with very cold water and submerged my head instantly. Within few minutes i began realising that the distention in my stomach and gut started going away. Within 7 minutes i was able to have some water and then began to feel that i wanted to eat. The parasympathetic response (="Rest and Digest") kicked in, dominating the SNS state i was stuck in.

Obviously one should proceed with extreme caution if wants to try this (discussed in the leaflet as well).

 

The Polish arm of Mortens study was looking at cryotherapy.

 

Exactly...i am also finding connections with thyroid function and thermogenesis.

 

I wanted to share this here as well from Phoenix Rising, December 2015 :




Liver Disease, Acetylcholine, Excitotoxicity, norepinephrine are in the chart. Brainstem was not part of the input data, or the Vagus nerve at the time.

Also PDHC, stands for Pyruvate Dehydrogenase Complex. Identified one year earlier before Flugge / Mella.

 

@mariovitali
I'm wondering if it is worthwhile doing one of your analysis of the lipids in the Hanson study and also mast cells. Thread here on the paper
https://www.s4me.info/threads/prosp...isease-symptomatology-2018-hanson-et-al.7090/

Supplementary file has Figure S1 - Box plot distribution of logged values for metabolites scored as being statistically different between controls (red) and patients (blue) according to the volcano plot tool from MetaboAnalyst. The first three seem to be lipids!

In my very primitive way of manipulating the Excel spreadsheet of raw data that was posted with the study to look at histamine the following additional metabolites seemed interesting in relation to histamine
taurodeoxycholate
perfluorooctanesulfonic acid (PFOS)
methyl glucopyranoside (alpha + beta)

I'm particularly interested in mast cells and the reported presence by some ME docs as 50% of ME patients having MCAS - there are blood borne markers for MCAS so this is not a number you can make up if you do the testing - but I wish there was a study to prove the number. We know many patients are sensitive to foods, supplements, medications, and a high percentage have IBS.

Could their be a link between mast cell degranulation, lipids, and IBS for a subset of ME patients. I don't remember seeing mast cells listed on your graphs, but maybe that is due to the lack or research on them?

 

This may be off topic and not relevant but the only test I have ever had that showed something wrong was during a study done looking at acetylcholine.

They used a doppler machine to measure the dilation of the blood vessels then dropped some acetlycholine on my arm. The acetylcholine was not cleared for much longer than in normal controls.

I have a lot of problems with my muscles twisting and going into spasm and I wonder if accumulation of acetylcholine is the cause.