Machine Learning-assisted Research on ME/CFS

@Ravn

I believe that HRV is a very important predictor so bought a heart monitor strap and connected it to my phone. I got my first reading (see attached) which is considered a low reading. I also stared a drug which was proposed through Machine Learning . I know all the signs that my body gives and so i will know within a few days. I expect also that the HRV will increase over the next period of time.

In any case this is really exciting, i will post updates.

@Trish @Andy do you think that HRV monitoring deserves a different thread?

F0DA7DA3-9363-40E2-8C33-0DE4C42F7A82.jpeg
 
Last edited:
mariovitali said:
@wigglethemouse this will take some time but sounds interesting. Where did you find an entry for methyl glucopyranoside ? Is it in the CSV file from the supplementary material?
Click to expand...
@mariovitali Yes the Excel file published with the paper here.
www.mdpi.com/2218-1989/8/4/90/s1

Here is how I analysed the data. I crudely sorted the data in the Excel file by difference in median values between patients and controls to see what was interesting. That's how I ended up with similar top metabolites to those in the Volcano plot analysis in the paper.

Histamine was near the top and I plotted it here. Histamine is one of the mediators released by mast cells. In this small data set it looked interesting to explore further.


I crudely removed controls with histamine >210K and removed patients with histamine <210K from the spreadsheet to see what other metabolites jumped out when I resorted that table by difference in median (tweet shows 200K, for the life of me I can't remember whether I used 200K or 210K). PFOS screamed at me when I did that. Strangely there is no mention of PFOS in the paper.


This is PFOS plotted with the original data (no removing any data)


I read the EPA and news articles surrounding PFOS and there seems to be quite a bit of sweeping under the carpet and many folks say the "safe" levels are set way way too high - even a White House report. Many studies have been done on PFOS/PFOA and it's known to affect the thyroid. I never looked to see if there is a known effect with the liver.....

Anyway, back to
- taurodeoxycholate
- perfluorooctanesulfonic acid (PFOS)
- methyl glucopyranoside (alpha + beta)

These appeared at the top of my second table when I crudely manipulated the data for histamine. They had the biggest jump from my original ranking by median difference in the first table to the rank in the second table
Rich (BB code): 
Orig  New   Rank    Metabolite
Rank  Rank  Change
6     1     5       histamine
2     2     0       pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC)
3     3     0       tauroursodeoxycholate
47    4    43       taurodeoxycholate
8     5     3       piperine
44    6    38       perfluorooctanesulfonic acid (PFOS)
34    7    27       methyl glucopyranoside (alpha + beta)
5     8    -3       3-hydroxybutyrylcarnitine (1)
16    9     7       heme
7    10    -3       3-hydroxybutyrate (BHBA)
14   11     3       taurocholate

This is the median/average values for the original data in my first table for methyl glucopyranoside
Rich (BB code): 
        Control Patient Difference
Median  231897  404242  1.743194177
Average 441114  485311  1.100192804

And this is it when I manipulated the data for the second table
Rich (BB code): 
        Control   Patient  Difference
Median   178085   519806   2.918861779
Average  365486   524010   1.433734473

I know it's very crude analysis, but I'm not a statistician. I could be way wrong in all this. Either way, thankful to Dr. Hanson and team for making the raw data available to play with.

Sorry if I rambled on too much in your thread.
 
Last edited:
So I guess my question is, if a large subset of patients are suspected to have mast cell degranulation issues, that could be indicated by the higher histamine values in some patients, can we use that knowledge to find other metabolites that may correlate, and what bodily systems are involved. From the top 10 shown in the table above bile acids and enviromental toxins could show a relationship to the liver. That's where I thought it would be interesting to get your take @mariovitali .
 
Australia's Neil McGregor looked at this dataset, I think, and it was part of his presentation at the recent Emerge conference. Link to where he talks about PFOS as well as other things.
Code: 
https://youtu.be/UvGMbbyGtvg?t=2076
copy and paste to go to the right time point in the video.
 
Andy said:
Australia's Neil McGregor looked at this dataset, I think, and it was part of his presentation at the recent Emerge conference. Link to where he talks about PFOS as well as other things.
Code: 
https://youtu.be/UvGMbbyGtvg?t=2076
copy and paste to go to the right time point in the video.
Click to expand...
Thanks @Andy. You've got a good memory! He also mentions 4-hydroxychlorothalonil a fungacide. I hadn't seen that in the data.

What I did see in the "histamine" data and couldn't figure out was 4-hydroxycoumarin another another fungal metabolite
https://en.wikipedia.org/wiki/4-Hydroxycoumarin

I hadn't dug deeper on 4-hydroxycoumarin before as the patient/control sample size is relatively small. Food for thought.
Rich (BB code): 

Original spreadsheet
        Control   Patient  Difference
Median  95676     75147    0.785426857

Histamine manipulated spreadsheet
        Control   Patient  Difference
Median  95676     194982   2.037935323
 
@wigglethemouse

I did try using specific ML techniques but i get incosistent results due to the small amount of data related to the number of features. I will look more on mast cells and get back to you.



Here is one interesting connection of tinnitus -a frequent symptom of PwME- with Vagal Nerve stimulation :


Non-invasive vagus nerve stimulation reduces sympathetic preponderance in patients with tinnitus.
Ylikoski J1,2, Lehtimäki J1,2, Pirvola U3, Mäkitie A4, Aarnisalo A4, Hyvärinen P4, Ylikoski M1,2.
Author information

Abstract
CONCLUSION:
Transcutaneous vagal nerve stimulation (tVNS) might offer a targeted, patient-friendly, and low-cost therapeutic tool for tinnitus patients with sympathovagal imbalance.

OBJECTIVES:
Conventionally, VNS has been performed to treat severe epilepsy and depression with an electrode implanted to the cervical trunk of vagus nerve. This study investigated the acute effects of tVNS on autonomic nervous system (ANS) imbalance, which often occurs in patients with tinnitus-triggered stress.

METHODS:
This study retrospectively analysed records of 97 patients who had undergone ANS function testing by heart rate variability(HRV) measurement immediately before and after a 15-60 min tVNS stimulation.

RESULTS:
The pre-treatment HRV recording showed sympathetic preponderance/reduced parasympathetic activity in about three quarters (73%) of patients. Active tVNS significantly increased variability of R-R intervals in 75% of patients and HRV age was decreased in 70% of patients. Either the variability of R-R intervals was increased or the HRV age decreased in 90% of the patients. These results indicate that tVNS can induce a shift in ANS function from sympathetic preponderance towards parasympathetic predominance. tVNS caused no major morbidity, and heart rate monitoring during the tVNS treatment showed no cardiac or circulatory effects (e.g. bradycardia) in any of the patients.
Click to expand...
 
@mariovitali , sorry if this is something you have tried and reported on already, but can you, and have you, used your software to search for papers in other research areas that report on mitochondrial functioning being inhibited due to a factor carried by the blood? I have a loose understanding on what is possible so don't worry about telling me it's a silly suggestion. :)
 
Andy said:
@mariovitali , sorry if this is something you have tried and reported on already, but can you, and have you, used your software to search for papers in other research areas that report on mitochondrial functioning being inhibited due to a factor carried by the blood? I have a loose understanding on what is possible so don't worry about telling me it's a silly suggestion. :)
Click to expand...

There are no silly suggestions @Andy :)


I believe you are referring on the "something in the blood" mentioned by Ron Davis. I did try to see what i can find but this is as if i am trying to work with one hand only and allow me to explain :

This software framework should be used in Tandem with experts that know what they are doing. It is the experts that should be guiding the process and not someone such as myself who has no background in Medicine, whatsoever.

No one was listening since 2015 @Andy. If acetylcholine is indeed central to ME/CFS pathology and this was identified since 2015 then...i will stop here. Allow me to say once more that i will work with everyone, starting tomorrow, who is able to evaluate the findings of this tool.

It's sitting there, waiting. I do not know how soon i will be able to give these findings to be put to use. If anyone can help, please PM me.
 
mariovitali said:
@wigglethemouse

I did try using specific ML techniques but i get incosistent results due to the small amount of data related to the number of features. I will look more on mast cells and get back to you.



Here is one interesting connection of tinnitus -a frequent symptom of PwME- with Vagal Nerve stimulation :
Click to expand...
I think there's a study of tVNS underway at Vanderbilt.
 
I made some really good progress today. It's all coming together when it comes to acetylcholine although it's very possible that this involves a subgroup of patients. We shall see.

I think the "liver disease" shown over and over in the algorithmic runs is there because without a proper liver function there is not much acetylcholine going around. The same when there is choline deficiency :

network copy.png


According to the following paper, there is a hepatic branch of the vagus nerve which is responsible to release acetylcholine



Targeting Cholinergic System to Modulate Liver Injury.
Jadeja RN1, Rachakonda VP2, Khurana S1,3.
Author information
1
Digestive Health Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States.
2
Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pennsylvania, United States.
3
Geisinger Medical Center, 100 N. Academy Ave. Danville, PA 17822-2111, United States.
Abstract
Over the past few decades, evidence accumulated to indicate that parasympathetic innervation regulates liver injury and regeneration. Liver derives its parasympathetic input via vagus nerve. In animal models, vagus nerve stimulation and transection are frequently used to determine the impact of parasympathetic input on liver injury responses. Such strategies provide limited understanding of postneuronal mechanisms involved in the regulation of liver injury. The hepatic branch of vagus nerve releases acetylcholine (ACh), which activates muscarinic and nicotinic receptors in hepatocytes as well as non-parenchymal cells to modulate cellular functions. Moreover, vagus nerve releases other neurotransmitters such as vasoactive intestinal peptide (VIP), which also modulates liver injury responses and hemodynamics. Therefore, our understanding of the post-neuronal modulation of liver injury in models utilizing vagus nerve activity remains limited. Gene-silencing technologies and pharmacological manipulation of receptor activity have not only improved our understanding of the role of specific cholinergic receptors but also elucidated the role of various liver cell sub-populations in modulating liver injury response. With advent of organ- and cell-specific transgenic mice, our understanding of neural regulation of liver injury is likely to improve further. This review comprehensively provides current understanding of cholinergic regulation of liver injury, and points to potential therapeutic targets to treat liver injury.
Click to expand...


In other words, could a liver injury is responsible for dysregulation of acetylcholine production? There may be serious consequences down the line for sure, one involving the cholinergic anti-inflammatory pathway (CAP). From Wikipedia :


Tumor necrosis factors (TNF) (and other cytokines) are produced by cells of the innate immune system during local injury and infection. These contribute to initiating a cascade of mediator release, and recruiting inflammatory cells to the site of infection to contain infection, referred to as "innate immunity.". TNF amplifies and prolongs the inflammatory response by activating other cells to release interleukin-1 (IL-1), high mobility group B1 (HMGB1) and other cytokines.[4] These inflammatory cytokine responses confer protective advantages to the host at the site of bacterial infection. A “beneficial” inflammatory response is limited, resolves in 48–72 hours, and does not spread systemically. The cholinergic anti-inflammatory pathway provides a braking effect on the innate immune response which protects the body against the damage that can occur if a localized inflammatory response spreads beyond the local tissues, which results in toxicity or damage to the kidney, liver, lungs, and other organs.[5]
Click to expand...



My HRV steadily rising, feeling much better , less bloated. I think i know why my health declined after i started dieting to shed some extra pounds. When lipolysis takes place, epinephrine kicks in and i probably do not want that (because it triggers the sympathetic nervous system !).

Regarding lipolysis. Observe "epinephrine" below :


400px-Metabolism1.jpg


Illustration of the activation of lipolysis in an adipocyte. induced by high epinephrine and low insulin levels in the blood. Epinephrine binds to beta-adrenergic receptors on the cell membrane of the adipocyte, which causes cAMP to be generated inside the cell.


I made more connections, will post in the next couple of days
 
Last edited:
obeat said:
@mariovitali . Are you aware that Systrom is trialling pyridostigmine? He's looking at cardio effect, but is there any way of looking at liver effect?
Click to expand...

Just posting this here too :

I hypothesise that Glutamate along with Liver disease may be the missing pieces of the puzzle *if* a subset of ME patients does not respond to an acetylcholinesterase inhibitor assuming that such a medication is found to be ameliorating ME symptoms to some patients.

I also hypothesise that Glutamate is not beneficial for the symptoms of PwME
 
Last edited:
Something of interest, Patients on Phoenix Rising used Cayenne and had some nasty side effects :

https://forums.phoenixrising.me/threads/spicy-foods.54052/

and

https://forums.phoenixrising.me/threads/cayenne-pepper-disaster-black-out.46227/

Is it possible that Cayenne -which contains capsaicin - disrupts cholinergic signaling ? Non-human studies :


Vagal nerve stimulation induced an increase in RL and a fall in CDYN. Significant changes in RL and DDYN (more than 50%) were still present after atropine, while the vagal heart response was abolished. Systemic or local capsaicin pretreatment abolished the atropine-resistant vagal effect on RL and CDYN. The atropine-sensitive changes in pulmonary mechanics upon vagal stimulation were significantly reduced by capsaicin pretreatment.
Click to expand...

https://link.springer.com/article/10.1007/BF00504379

May be something to look for.
 
Last edited:
@wigglethemouse

I found the following connection for MCAS which i believe you are interested in :


A tryptophan metabolite, kynurenine, promotes mast cell activation through Aryl hydrocarbon receptor

Tryptophan metabolites have been suggested to play a role in immune modulation, wherein those have recently been shown to be endogenous ligands of aryl hydrocarbon receptor (AhR; a unique cellular chemical sensor). However, the involvement of tryptophan metabolites and AhR in modulating mast cell function remains to be fully defined. We therefore investigated that the functional impacts of tryptophan metabolites on human and mouse mast cell responses in vitro and their functional importance in vivo. Three tryptophan metabolites, kynurenine (KYN), kynurenic acid (KA) and quinolinic acid (QA), were examined in terms of their effect on IgE-mediated responses in mouse bone marrow-derived mast cells (BMMCs) and in human peripheral blood-derived cultured mast cells (HCMCs) and on in vivo anaphylactic responses. For evaluation of AhR involvement, we examined the responses of mast cells from AhR-null or AhR-wild-type mice with the use of a known AhR antagonist, CH223191. Kynurenine, but not KA and QA, enhanced IgE-mediated responses, including degranulation, LTC4 release, and IL-13 production in BMMCs through the activation of PLCγ1, Akt, MAPK p38, and the increase of intracellular calcium. KYN also enhanced cutaneous anaphylaxis in vivo. These enhancing effects of KYN were not observed in AhR-deficient BMMCs and could be inhibited by CH223191 in BMMCs. Further, KYN had similar enhancing effects on HCMCs, which were inhibited by CH223191. The AhR-KYN axis is potentially important in modulating mast cell responses and represents an example of AhR's critical involvement in the regulation of allergic responses.
Click to expand...


The work of Robert Phair becomes -potentially- increasingly important for other reasons as well (based on my research).


https://www.researchgate.net/public..._activation_through_Aryl_hydrocarbon_receptor
 
Last edited:
I believed that i lost this one but i am glad i was wrong : Over the past days i am seeing a very significant improvement in word-finding and memory. The difference is very noticeable because i am able to recall compounds that i read very recently, something which i simply couldn't do.

I am gathering all the papers related to Kynurenine metabolism and will post here. I will also give a hypothesis on why i had a severe decline in my health and how all of this may be connected. If i had to "put my money" on current research, i would choose Robert Phair and Petter Brodin from Karolinska.

One example : Kynurenine metabolism and Liver fibrosis (in rats) :

Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach


Changes in amino acids and their metabolites. We identifed metabolites, including L-tryptophan, kynurenic acid, 5-hydroxyindoleacetyl glycine, and 3-methyldioxyindole, 4-(2-amino-3-hydroxyphenyl)-2,4 -dioxobutanoic acid in urine are by-products of tryptophan metabolism.The model group showed markedly elevated urinary L-tryptophan at weeks 6 and 8 and significant decreases in four other metabolites at all time points, suggesting a disturbance of tryptophan metabolism during the onset and evolution of liver fibrosis

<SNIP>

Finally, nine crucial metabolites in urine were identified from these selected metabolic pathways as follows: five metabolites (L-tryptophan, kynurenic acid, 4-(2-amino-3-hydroxyphenyl)-2,4 -dioxobutanoic acid 5-hydroxyindoleacetylglycine, and 3-methyldioxyindole) are metabolic products of the tryptophan metabolic pathway; two metabolites (cis-aconitic acid and isocitric acid) belong to the TCA cycle and gly- oxylate and dicarboxylate metabolic pathways; and two metabolites (L-leucine and methylmalonic acid) belonged to the valine, leucine and isoleucine degradation pathways.
Click to expand...


https://www.nature.com/articles/s41598-017-11759-z
 
You must log in or register to reply here.
Back
Top Bottom