Machine Learning-assisted Research on ME/CFS

IAP is a major regulator of gut mucosal permeability
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That seems to come up a lot. The presence of bacteria in the blood after exercise is hard to explain otherwise, they have to come from somewhere. I assume this would lead to a low-level sepsis response.

Normally, inflammation dilates blood vessels, right? But there seems to be something about activating the ANS that is failing, leading to the dysautonomia experienced by, it seems, most patients, at least to a point. The pre-load failure mentioned by Systrom. Blood vessels dilated by inflammation, unable to constrict as needed to supply to capillaries. Anyway, just a hypothesis.

It seems to possibly boil down to active processes that normally are in balance but something in failing in compensating mechanisms. If so, the process would be very difficult to pinpoint from any static tests or blood panels and could explain why we haven't yet.
 
I was wondering if there are ME/CFS patients that have pharmacogenic SNPs to VKORC1 (warfarin response). I have 3 homozygous. Another severely ill patient has also 3 (on different VKORC1 genes). Here they are :

I very recently got my full genome from Dantelabs so i was able to look mine.


cc @wigglethemouse

Myself (all homozygous) :

s2884737
rs8050894
rs9934438


Severely ill patient (all homozygous) :
rs7294
rs2359612
rs7196161


Screen Shot 2019-10-14 at 12.33.11.png Screen Shot 2019-10-14 at 12.32.54.png Screen Shot 2019-10-14 at 12.31.08.png


Full list :


http://www.disgenet.org/browser/1/1/2/79001/
 
In case it's useful to you, @mariovitali, here are my snps on VKORC1. Intriguingly similar to yours.

FWIW my blood is too "thick" if anything, the nurses always complain about it. So on the face of it it seems counterintuitive that I would only require low doses of warfarin to thin it, but there could well be two separate mechanisms involved.

rs2884737 heterozygous

rs8050894 homozygous

rs9934438 homozygous
 
Ravn said:
In case it's useful to you, @mariovitali, here are my snps on VKORC1. Intriguingly similar to yours.

FWIW my blood is too "thick" if anything, the nurses always complain about it. So on the face of it it seems counterintuitive that I would only require low doses of warfarin to thin it, but there could well be two separate mechanisms involved.

rs2884737 heterozygous

rs8050894 homozygous

rs9934438 homozygous
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I had the same problem which i believe originated from high homocysteine. When i had more severe symptoms it was the other way around : Blood would not clot easily and also wounds would take much more time to heal than usual.
 
wigglethemouse said:
@mariovitali
Have you checked out this warfarin dosing calculator site. Some variants have a positive effect, and some negative.
http://www.warfarindosing.org/Source/Home.aspx

Some more info on the ARUP test site
http://ltd.aruplab.com/tests/pub/3001541

Some more genetic pharmacogenic testing info here
https://www.ncbi.nlm.nih.gov/books/NBK52750/
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Thank you @wigglethemouse , following the second link (ARUP) i realised that i have more SNPs to warfarin response apart from VKORC1, namely CYP4F2, CYP2C8, CYP2C9

What i do not know is how common such a setup might be (ie having so many SNPs to warfarin response) and whether it is clinically significant. It seems that I will still have to wonder whether case 202 may be telling us something regarding ME/CFS and warfarin response :

https://solvecfs.org/wp-content/uploads/2014/01/IOM_RoadtoDiagnosisSurveyReport.pdf
 
mariovitali said:
What i do not know is how common such a setup might be (ie having so many SNPs to warfarin response) and whether it is clinically significant. It seems that I will still have to wonder whether case 202 may be telling us something regarding ME/CFS and warfarin response :
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The first link gives a personalised dosing calculator that takes into effect the various mutations and from that gives you an adjusted dosing that you can use to take a guess how clinically significant they are in your own case. Calculator is rather difficult to use and if I remember right you need to convert hg18 to hg19 references. dbSNP gives variants for both references. Calculator is intended for medical boffins I think.
http://www.warfarindosing.org/Source/Home.aspx
 
cc : @Perrier

Thank you for this info @wigglethemouse. I plugged in the numbers given the information on the PDF you provided. Here is the snapshot of my estimated dose but please have in mind that i had to plug two numbers (Baseline INR, Target INR) for which i was not sure. I believe that this is a quite low dose (3.3 mg - the 4.5 shown is for initial 1-2 days) :

Screen Shot 2019-10-17 at 12.02.40.png


I will have to make calculations for the severely ill patient and -if the patient agrees- post them here.
 
mariovitali said:
I believe that this is a quite low dose (3.3 mg - the 4.5 shown is for initial 1-2 days) :
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@mariovitali
When I played with the tool I compared the actual dose with a "no-variants" dose. i.e. a dose where the reference allele was used. That method might provide you with a little more context..... then again I didn't see much difference so gave up........ I'm guessing that perhaps the patient details entered on the first screen also play a role in how much change you can expect to see from the variants.......
 
Good thinking there @wigglethemouse . I did something similar , changing the parameters for Liver disease (for obvious reasons!) but not the extended testing you did. Didn't change much at all, so yes we may have to find another algorithm.

Just wanted to say : Thank you for all the "reality checks" you are doing. It is painstaking but absolutely necessary. Thank you once again !
 
In seeing @Andy 's latest posts regarding mitochondrial fusion/fision, i wanted to share some thoughts.

It was @wigglethemouse that reminded me about DRP1 and P53 by sharing some slides and so yesterday i started looking to try to connect more dots. It appears that there is a connection of DRP1 with excitotoxicity. I believe that this -if this is applicable- is a major finding that supports even more the hypothesis that glutamate metabolism and/or excitotoxicity is a central aspect of ME/CFS pathology. More specifically :

From : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339882/

we read :

Second, glutamate excitotoxicity causes mitochondrial fission through a Drp1-independent mechanism in primary hippocampal cultures (Young et al., 2010). Furthermore, inhibition of calcineurin-mediated activation of Drp1 and mitochondrial fission prior to deprivation of oxygen and glucose improves neuronal survival but does not prevent mitochondrial fission during and following injury (Slupe et al., 2013). If inhibition of Drp1 does not prevent ischemia-induced mitochondrial fission, how does it mediate neuroprotection? Mitochondrial fission is thought to sensitize neurons to insults, such as oxidative stress and excitotoxicity, because the subsequent decrease in the ability of the fragmented mitochondria to produce ATP ultimately impairs their capability to detoxify excess ROS and sequester or extrude intracellular Ca2+ (Reddy et al., 2011). In support of this, knockdown of MCU prevents NMDA-mediated excitotoxicity induced mitochondrial depolarization and improves neuron survival (Qiu et al., 2013). Similarly, promotion of mitochondrial elongation prior to injury through inhibition of Drp1 could improve neuronal survival as it increases mitochondrial membrane potential and, in turn, bioenergetic capacity, helping neurons weather an ischemic energy crisis (Fig. 3).
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also, we have :

DRP1 + Mito fission + NLRP3 (inflammasome) + activation of T-Cells

https://www.researchgate.net/figure...esponses-Mitochondrial-fission_fig5_326347468

I will contact today SolveCFS and ask for this information to be forwarded to Dr Bhupesh Prusty. I will update you all.

More info on Dr Prusty :


https://solvecfs.org/dr-bhupesh-prusty/
 
I wanted to report an SNP that i have, after receiving my full genome data. It is PRODH (Proline Dehydrogenase). It is rs2904552 which gives me a susceptibility to hyperprolinemia type I


I will have myself checked on high serum proline levels and report back here. This may be potentially important because of a connection of proline with glutamate and inflammation :

The excess of glutamate elicited by Pro together with increased glutamate uptake and upregulated glutamine synthetase (GS) activity supported misregulated glutamate homeostasis in astrocytic cells. High Pro levels also induced production/release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. We also evidenced misregulation of cholinergic anti-inflammatory system with increased acetylcholinesterase (AChE) activity and decreased acetylcholine (ACh) levels, contributing to the inflammatory status in Pro-treated astrocytes. Our findings highlighted a crosstalk among disrupted glutamate homeostasis, cholinergic mechanisms, and inflammatory cytokines, since ionotropic (DL-AP5 and CNQX) and metabotropic (MCPG and MPEP) glutamate antagonists were able to restore the extracellular glutamate and glutamine levels; downregulate TNFα and IL6 production/release, modulate GS and AChE activities; and restore ACh levels
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https://www.ncbi.nlm.nih.gov/pubmed/25579384
 
cc @Perrier

cc : @Simon M

Based on the fact that SS31 changes the impedance of the nanoneedle with a bit of searching i found the following :



1) SS31 upregulates SIRT1 and PPARGC1A
https://www.hindawi.com/journals/omcl/2018/4783602/


2) Glutamate and aspartate downregulate PPARGC1A
https://link.springer.com/article/10.1186/1743-7075-10-44



3) PPARGC1A shown in the EUROMENE representation i gave in September 2018 at the LSHTM, observe also lactate and the fact that is induced by cold. Also Resveratrol induces it :

PGC1A.png


4) PGC1 shown in the Network Analysis generated in 2017


network2017.png
 
wigglethemouse said:
@mariovitali
Have you checked out this warfarin dosing calculator site. Some variants have a positive effect, and some negative.
http://www.warfarindosing.org/Source/Home.aspx

Some more info on the ARUP test site
http://ltd.aruplab.com/tests/pub/3001541

Some more genetic pharmacogenic testing info here
https://www.ncbi.nlm.nih.gov/books/NBK52750/
Click to expand...

This may be of some use - Cytochrome P450 and drug interaction ( Flockhart table)
https://drug-interactions.medicine.iu.edu/MainTable.aspx
 
Yesterday i saw the following Tweet by Dr Guthridge :


Screen Shot 2020-02-05 at 11.36.26.png



Regarding Dr Guthridge : https://me-pedia.org/wiki/Mark_Guthridge


Statins have long been suspected and identified using Network Analysis (one of the methods i use for ME Research). We connected with Dr Guthridge (after a tweet i made) and asked me to sent him whatever hypotheses i have generated using Machine Learning.

I also sent him a document which i e-mailed to Dr Davis and Professor Hanson in October 2017 with specific cautions on statins and HmG-CoA inhibitors in general (as a hypothesis). The proposed mechanism is disruption of the mevalonate pathway and disruption of N-Linked Glycosylation.

Fingers crossed.
 
We sometimes see articles in the journal Medical Hypotheses which use all sorts of different data to hypothesise what is going on in ME. Would it be possible for you to write up your hypothesis and submit it for publication?
 
Trish said:
We sometimes see articles in the journal Medical Hypotheses which use all sorts of different data to hypothesise what is going on in ME. Would it be possible for you to write up your hypothesis and submit it for publication?
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Yes this would be a useful action. What worries me is that in this case as well, i do not have the medical knowledge to present a solid hypothesis. I only get elements that have to be put together by people that know what they are doing. I was happy when CureME team supported me in submitting a proposal to SolveCFS because i would have professionals that would help implement a scientifically solid methodology and hypotheses.

If this doesn't exist, i believe that the effort is doomed to fail. What i can do from my side is to show these elements, explain why these elements may be important and then it is up to the experts.
 
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