Machine Learning-assisted Research on CFS

[mariovitali]

@Hip

CC @Jesse2233

Please read the following e-mail i received from a Professor who i will not disclose :

Dear .....,


This is all very interesting indeed! I’m not involved at the moment in machine learning techniques, but I am totally convinced that they have a future in Medicine and in Research. I wish I could understand this technique better, as I have problems with a few approaches, such as how do you handle lots of unfruitful research on a specific topic. Or how do you actually take into account good research and not just speculations. But, it is just ignorance. I’m used to the methods of systematic review and meta-analysis and for me this sounds like meta-analysis without the critical part.


I see some interesting uses, however, like those related to behavioural changes. I know a group in ----- (.... .... is involved) who is developing apps for ------ ------ patients based on it.


Also for diagnostic or prognostic algorithms. All the other uses in ---- look just great also.


I’m eager for you to introduce me into the world of Machine learning.


As a first step, would you be willing to write a review for ---------- on potential uses of Machine Learning in -------? That would be great and would allow me to disseminate your work among ----------.

I will not get into the argument on whether this Professor is a true Scientist or not. But i cannot but commend the attitude where we have on one hand Specific concerns being presented that require attention but on the other hand not readily dismissing a new technology.

I do understand what Professor Edwards meant but there is also a possibility that given the amount of information, such bias gets "cancelled out" so to speak.

But please, allow me to elaborate further : Given the fact that there is a lot of garbage out there (but also non-garbage) we have a set of Hypotheses being created using some Analytical techniques.

I have repeatedly asked Proffessor Edwards to comment on the output (=Hypotheses) that originated from these techniques and whether the hypotheses being generated could be valid. He never replied despite my repeated questions. If you could comment on why this is so (and even better him doing so) it would be great. For all of us.

I am providing some links to these dialogs :
http://forums.phoenixrising.me/inde...sted-research-on-cfs.51283/page-4#post-853658
http://forums.phoenixrising.me/inde...sted-research-on-cfs.51283/page-4#post-853658

and

http://forums.phoenixrising.me/inde...sted-research-on-cfs.51283/page-4#post-853607

and

http://forums.phoenixrising.me/inde...sted-research-on-cfs.51283/page-4#post-853727

 

[Hip]

But please, allow me to elaborate further : Given the fact that there is a lot of garbage out there (but also non-garbage) we have a set of Hypotheses being created using some Analytical techniques.

Can you discuss those hypothesis-creating techniques, or are they your own proprietary algorithms that you wish to keep secret?

If I were writing your software algorithm, I would run the algorithm on diseases that we have recently discovered the cause of, but restrict the algorithm to papers published before the cause was known. Then you could see how many times your algorithm guesses right. In other words, run your algorithm on historical data that we already known the answer to, and see if your algorithm comes up with the right answer. That would be impressive if it could.

I wrote some predictive software many years ago, and I tested out in this way, using historical data that we know the results of: in my MSc in cognitive science, in my project I was using computer neural networks to model brain function. Just for fun, I decided to write a neural network-based prediction algorithm for the football pools (the lottery based on guessing the results of UK football matches). I trained my neural network using past football match data, and then I tested its ability to of my neural network to predict some further past football games (which the network had never seen). I found, incidentally, that my neural network was able to predict the correct football result 10 times better than chance alone, but this was not sufficient to stand a reasonable chance of winning the football pools.

So you could the same thing, and test your algorithm on historical data.

I find the idea of your algorithm very interesting; but without some demonstration of its abilities, using historical data in the way I described, it remains an unproven idea.

I have repeatedly asked Proffessor Edwards to comment on the output of these techniques and whether the hypotheses being generated could be valid.

It takes many months (if not years) of effort and brain powder to understand the connection that any given pathway may or may not have to ME/CFS (or any other disease for that matter). Most medical researchers have specialized areas of biomedicine that they know a lot about, and they usually also have a broad, but less in-depth, understanding of biomedicine in general.

So what you are asking is for someone to drop their current activities, and devote several months to investigating some pathway that your algorithm has suggested. And without any evidence that it is the right answer. You might find some researchers willing to do that, but I expect most will not, as they have their own interests.

Especially as your algorithm provides no context. For example, you say your algorithm picked up on pyruvate dehydrogenase before Fluge and Mella discovered a possible dysfunction in PDH. But with Fluge and Mella's investigations, we see the entire context in which PDH fits in, so you can understand the whole picture.

But if your algorithm just points to PDH without any context, it's hard to know what to make of it. If your algorithm were to throw out say "alpha lipoic acid", there are thousands of pathways that might potentially be involved; without providing any further context, how is a researcher going to begin to guess how ALA might be linked to ME/CFS?

If you were able to extract a bit of context from your algorithm, that would help I think. I don't know how your algorithm works, so don't know if providing context would be possible, but it would be helpful. As would validating your algorithm on diseases with known causes.

 

[mariovitali]

@Hip

See my comments inline :

Can you discuss those hypothesis-creating techniques, or are they your own proprietary algorithms that you wish to keep secret?

I think we must first define what is "hypothesis" here. The system extracts Topics that are most likely related to a certain condition. It does not generate a complete hypothesis in the way that -if my understanding is right- you describe. As you also noted, the system does not provide context. In other words we do not know if Tocotrienol is good or bad for us. However in our case, the system identifies several Topics that are part of specific pathways (e.g Bile Acids, Glucolysis). Both of these are related to the Liver so this is a Hypothesis being generated based on these Topics.

If I were writing your software algorithm, I would run the algorithm on diseases that we have recently discovered the cause of, but restrict the algorithm to papers published before the cause was known. Then you could see how many times your algorithm guesses right. In other words, run your algorithm on historical data that we already known the answer to, and see if your algorithm comes up with the right answer. That would be impressive if it could.

I agree with this practice. However, please have in mind that i was ill and developing this system at the same time. My health was deteriorating very rapidly. I was found being in a pre-diabetic state, Hypothyroid and with many other issues. You are talking about "backtesting" the system which is a standard practice in Machine Learning. I also feel that the rate with which the system puts pieces together is not linear (if this makes sense to you) so going back 10 years may affect the system's performance way much more than going back 2 years.

So what you are asking is for someone to drop their current activities, and devote several months to investigating some pathway that your algorithm has suggested. And without any evidence that it is the right answer. You might find some researchers willing to do that, but I expect most will not, as they have their own interests.

This is not the case. I presented to Professor Edwards a series of Papers pertinent to MERTK , GAS6 and some other Genes related to Vitamin K metabolism. If my memory serves me well, back then the system was looking at almost 600 Topics, it selected 4 of them and all 4 had functions related to autoimmune disease. The comment i asked by Professor Edwards was for this fact, i did not ask him to assess the whole Theory.

Especially as your algorithm provides no context. For example, you say your algorithm picked up on pyruvate dehydrogenase before Fluge and Mella discovered a possible dysfunction in PDH. But with Fluge and Mella's investigations, we see the entire context in which PDH fits in, so you can understand the whole picture.

I think that the system not only described PDH before Fluge/Mella but also Phospholipids and Bile Acids as found by Naviaux. I must also see if PPARγ importance was found before Fluge/Mela. Regarding the lack of context you describe, this is correct. The system is meant to be used along with Researchers who have the responsibility to generate a complete Hypothesis. But imagine how helpful a system would be that gives you a guidance and enables you to focus on the root of the problem (hopefully) and not to an area that has nothing to with the Research Topic at hand.

 

[mariovitali]

Here is a quick update and the latest Network Analysis graph:

We take note of the following :


-The important roles of NAD and Tocotrienol (it is not suggested to take supplemental Tocotrienol)

-How glycosyltransferases connect Endoplasmic Reticulum Stress/ Unfolded Protein Response topics (under Green rectangle) and more central topics such as NAD and Tocotrienol.

-We note also the role of Glycoproteins (Red rectangle) with Topics related to Inflammatory Processes.

-There is also a part on the Network (not shown) which has many Liver-related Topics.

Glycosyltransferases may be a possible marker for ME/CFS.

Apart from Network Analysis, there is an increasing ranking in the importance of GRB2 and SH2B3 (more coming soon regarding these two genes)

 

[aquariusgirl]

Mario: the moderators @ Low Oxolates group recognize the syndrome comes w/gallbladder problems.

But they haven’t figured out the mechanism.

 

[mariovitali]

@Violeta

Can you provide a link please?

 

[aquariusgirl]

@mariovitali .'.Trying Low Oxolates is a closed facebook group so not sure I can. In her post on iron , Alethea suggest that B1 uses up manganese. Maybe there is a connection there?

 

[aquariusgirl]

@mariovitali

There is a line of research that associates low zinc with various pyschiatric problems. I read that zinc supplementation is being advised for those with treatment resistant depression.

Ok, so what has this got to do with CFS? Well this paper below suggests there are genetic variants in certain zinc transporters that result in low intracellular zinc even in the presence of normal serum zinc. The zinc/copper ratio is an issue in most neurological disease....and certainly there is a zinc, b6, oxalate connection.

"Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range."
" In addition, zinc is an agonist for GPR39 activation and for mTOR (mammalian target of rapamycin) (Szewczyk et al., 2015). "

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492454/

I also note that one of these zinc transporter genes has been associated with Ehlers Danlos.
https://www.ncbi.nlm.nih.gov/pubmed/18985159/

 

[mariovitali]

Here is a quick update everyone.


We have a new recovery

I got the OK from this person to share his real name and DNA Data to the OMF. I sent this information to Janet Dafoe just today.

This person had mid-to-severe symptoms of ME/CFS for 3 years. At times he had severe symptoms. He followed a personalized regimen for 5 months. What is really interesting with this particular case is that for the past 3 months he receives no treatment and despite this he has no symptoms. Of course we do not know if this will last.

I believe that giving his data to OMF is imporant, since they may be able to identify differences between patients having remission of symptoms vs patients with no remission.


Research-wise : we have an increasing importance of Omega-3 fatty acids mainly through the fact that they induce Peroxisome Proliferator PPARγ.

I will post more when i find some time.

 

[Gondwanaland]

@mariovitali please do a search for delta-6-desaturase

 

[aquariusgirl]

Why don’t you share their story here?

 

[mariovitali]

@Gondwanaland

This is a good catch. I already have added the relevant gene under consideration. You can see the discussion here :

(Scroll down until you see FADS2 in the list of concepts).


http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-83#post-743960

I do not seem to have looked however for possible SNPs about this Gene (and also FADS1) among the sample of DNA Data i have.



I will let you know.

 

[Gondwanaland]

I do not seem to have looked however for possible SNPs about this Gene (and also FADS1) among the sample of DNA Data i have.

I don't think it is genetic, I believe it is environmental

 

[Gondwanaland]

In any case, the genes for the pathway are here:
http://www.uniprot.org/uniprot/?query=organism:9606+pathway:436.658

 

[aquariusgirl]

https://www.biorxiv.org/content/biorxiv/early/2017/12/22/237958.full.pdf

https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=Graphics&list_uids=29957

 

[mariovitali]

All,

Here is the latest update regarding the Research for ME/CFS using Machine Learning Methods.


I start with the latest Network Analysis output :

We see three areas where a lot of Topics accumulate named 1,2,3.

Area 1 : Liver-related Topics such as NAFLD, Steatohepatitis, Liver Injury, Cholestasis, Liver Fibrosis and also Vitamin K, Urea Cycle, LXR Receptor, CYP27A1 etc

Area 2 : NAD, Tocotrienol, Glycosyltransferases. Note : The potential importance of Glycosyltransferases has been previously communicated to @Janet Dafoe (Rose49)

Area 3 : Topics related to Inflammation and Inflammatory Processes.


This is a zoom-in at Area 1 :

and Area 3 :

Note that the Node named DAMP refers to Danger-associated Molecular Pattern and also the Node named Lymphocyte-Adapter Protein


Unfortunately to this day, i do not know if the possibility of Liver Disease has been ruled out and if so, on what grounds. To the best of my knowledge, no Fibroscan tests and no Liver Biopsies were performed to ME/CFS patients so far. Liver panels cannot rule out Liver Disease.


My understanding also is that Ron is now considering that multiple pathways are in play. If this is so -according to the hypothesis presented here- this is a huge step forward.

This is a snapshot from a 29-page document i sent to @Janet Dafoe (Rose49) on October 2017 :

Also, we had a case of full recovery. The DNA Data along with his Full Name/Surname have been forwarded to @Janet Dafoe (Rose49). Interestingly, this indivdual had a Hepatitis incident years before his ME/CFS and also removed his Gallbladder. These obviously suggest Liver issues before his onset of ME/CFS.

The latest addition is an individual i met some days ago with Fibromyalgia Symptoms : He had Liver Biopsy 16 years ago that showed NASH (Non-alcoholic Steatohepatitis). Upon asking him why he had the Biopsy he said that he had constant Pain in the Liver Area. I will try to find his tests and send them over here and to Janet.

 

[mariovitali]

Here is a significant update regarding my effort to identify possible targets of ME/CFS and several other Medical Syndromes.


The Latest algorithmic run identifies Creatine Kinase as a significant Topic that requires further investigation :

Also : Albumin becomes a Major Target for further investigation


We see several known Topics (Glycoproteins, Inflammatory response / Cytokines, Oxidative Phosphorylation but also Creatine Kinase.


From Wikipedia some interesting excerpts :

Creatine kinase (CK)—also known as creatine phosphokinase (CPK) or phospho-creatine kinase—is an enzyme(EC 2.7.3.2) expressed by various tissues and cell types. CK catalyses the conversion of creatine and utilizes adenosine triphosphate (ATP) to create phosphocreatine (PCr) and adenosine diphosphate (ADP). This CK enzyme reaction is reversible and thus ATP can be generated from PCr and ADP.

In tissues and cells that consume ATP rapidly, especially skeletal muscle, but also brain, photoreceptor cells of the retina, hair cells of the inner ear, spermatozoa and smooth muscle, PCr serves as an energy reservoir for the rapid buffering and regeneration of ATP in situ, as well as for intracellular energy transport by the PCr shuttle or circuit.[2]Thus creatine kinase is an important enzyme in such tissues.[3]

Clinically, creatine kinase is assayed in blood tests as a marker of damage of CK-rich tissue such as in myocardial infarction (heart attack), rhabdomyolysis (severe muscle breakdown), muscular dystrophy, autoimmune myositides, and acute kidney injury.[4]

CC : @Janet Dafoe (Rose49) and @Jesse2233

I am also expecting results from several individuals that will have Fibroscans. All the above will be communicated to Robert Phair who is helping out the OMF Research for ME/CFS.

 

[mariovitali]

The more i look into Creatine, the more interesting it gets.


Some excerpts :

Sustained ATP levels are critical to cellular homeostasis and may have both direct and indirect influence on pathogenic mechanisms associated with neurological disorders. Creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease.

Creatine, through its metabolite phosphocreatine, provides a cellular reserve of high-energy phosphates

Recall mentions about impaired Oxidative Phosphorylation (OXPHOS) in ME/CFS?

Creatine (methylguanidino-acetic acid) is a guanidino compound synthesized endogenously from arginine, methionine, and glycine, predominantly in the liver, as well as in the kidneys, pancreas, testes (Bloch and Schoenheimer, 1941; Persky and Brazeau, 2001; Walker, 1979), and the brain (Braissant et al., 2001). Creatine is also derived exogenously through the diet in the consumption of meat and fish (Balsom et al., 1994). In order to maintain sufficient body stores of creatine, approximately 2 g are required daily through both diet and endogenous synthesis

The Liver mentioned once again. Again and again...

Increasing creatine levels may, therefore, help to prevent reduced energy stores and improve neuronal function. Creatine is also involved in regulating glycolysis, stabilizing the mitochondrial, octameric form of creatine kinase, and inhibiting the mitochondrial permeability transition pore (O’Gorman et al., 1996, 1997). The opening of the mitochondrial permeability transition pore is associated with both apoptotic and necrotic cell death mecha- nisms (Bernardi et al., 1998). Another potential neuroprotective mechanism of creatine supplementation is the ability of PCr to stimulate synaptic glutamate uptake and thereby reduce the accumulation of extracellular glutamate and the potential for excitotoxicity

Some interesting mentions about Creatine here on PR :


http://forums.phoenixrising.me/inde...ponsible-for-my-pem-relief.56729/#post-942902

and

http://forums.phoenixrising.me/index.php?threads/creatine-supplementation-reduces-my-pem.29061/

 

[Violeta]

The more i look into Creatine, the more interesting it gets.


Some excerpts :







Recall mentions about impaired Oxidative Phosphorylation (OXPHOS) in ME/CFS?



The Liver mentioned once again. Again and again...




Some interesting mentions about Creatine here on PR :


http://forums.phoenixrising.me/inde...ponsible-for-my-pem-relief.56729/#post-942902

and

http://forums.phoenixrising.me/index.php?threads/creatine-supplementation-reduces-my-pem.29061/

I just found this bit of information about creatine and phosphorus as related to vitamin c.

http://www.jbc.org/content/165/2/657.full.pdf

Several investigators (11, 12) have also reported a decreased phosphocreatine content in the muscle of guinea pigs in the terminal stages of vitamin C deficiency. However, no complete study of all the compounds involved in muscular

 

[mariovitali]

@Violeta

Things are not that easy. if someone having hemochromatosis takes Vitamin C then problems will occur because Vitamin C enhances iron absorption. When you have Hemochromatosis you don't want that.

The primary Goal then, is to find the Liver stressor which may have many different etiologies.