Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

[rvallee]

the whole concept of "catastrophizing" does not seem appropraite for people who are actually sick. The scales seem to presume that the fatigue or pain or whatever is not so bad as to warrant "catastrophizing." These scales have been used by the Chalders of the world to psycho-pathologize sick people. They tie it in with "fear avoidance" behavior, which to them represens "catastrophizing" rather than people having a realistic appraisal of their fatigue/pain symptoms and how they respond to activities. The idea that sick people are catastrophising is like blaming them for being sick and blaming their sickness on the fact that they are purportedly catastrophizing. Their reasoning is backwards.

Their 'reasoning' is "illness without disease". It satisfies the surrounding if(x) statement where x = we are not actually ill.

They often say that they believe we are experiencing the symptoms we think we are, but they only mean by that that we do have psychological conversion of distress and/or fear and/or catastrophizing and/or whatever where it feels like we perceive those symptoms. But of course they lie. A lot. They have to. Their entire models are built on a lie, derived from an original failed conditional.

Everything else is consistent with their beliefs. It makes no sense because it doesn't bother making sense. Models like this are very easy to destroy in a single move, so their only hope is to keep repeating the same nonsense, knowing that almost no one else in the profession cares, and that science and technology does not invalidate their models. Which will inevitably happen, but until then the delusions reign.

 

[bobbler]

the whole concept of "catastrophizing" does not seem appropraite for people who are actually sick. The scales seem to presume that the fatigue or pain or whatever is not so bad as to warrant "catastrophizing." These scales have been used by the Chalders of the world to psycho-pathologize sick people. They tie it in with "fear avoidance" behavior, which to them represens "catastrophizing" rather than people having a realistic appraisal of their fatigue/pain symptoms and how they respond to activities. The idea that sick people are catastrophising is like blaming them for being sick and blaming their sickness on the fact that they are purportedly catastrophizing. Their reasoning is backwards.

Thing is, the question ‘I want my fatigue to go away’ and the like is NEITHER

what person who has fatigue could answer anything other than yes to that? - it’s a no win leading question depending only on whether you have fatigue

and not depending at all on anything mental

what does saying ‘no id like my fatigue to stay like this and get worse forever’ ACTUALLY mean?

and how can someone who doesn’t have fatigue be qualified to answer this? There is nothing to stay or go..,

so most of these don’t even test whether someone is thinking about their illness in any rumination sense just answering questions they’ve been asked about not even how they perceive their symptoms but … well what?

do they ask people who’ve broken their leg if they want their leg pain to lessen

or if they want their leg to heal straight and work

and interpret that as … what?

it’s utter game-playing weaponising of the term/job description mental health with which responsibility should be encumbent to just ask any old thing that has no indicator at all re: mental anything. The only thing it can be answered on the basis of is real medical symptoms

so it’s a psychologising/misogynising/bugiting scale that asks about medical symptoms in questions that aren’t mental health dependent or influenced them claims if someone has ‘faituge’ or an injury that ‘you’d naturally like to heal or be sorted’ somehow that’s psychopathology on the basis of the interviewers assumption the fatigue or broken leg doesn’t exist? Even if it does?

what a weird choice if scale.

it’s like a physical illness —> psych illness currency converter by simply if you are conned enough to put a pencil to paper on it if you have a physical condition. So naughty ?

 

[bobbler]

Their 'reasoning' is "illness without disease". It satisfies the surrounding if(x) statement where x = we are not actually ill.

They often say that they believe we are experiencing the symptoms we think we are, but they only mean by that that we do have psychological conversion of distress and/or fear and/or catastrophizing and/or whatever where it feels like we perceive those symptoms. But of course they lie. A lot. They have to. Their entire models are built on a lie, derived from an original failed conditional.

Everything else is consistent with their beliefs. It makes no sense because it doesn't bother making sense. Models like this are very easy to destroy in a single move, so their only hope is to keep repeating the same nonsense, knowing that almost no one else in the profession cares, and that science and technology does not invalidate their models. Which will inevitably happen, but until then the delusions reign.

I’ve no idea how they blagged validity claims when it’s just about internal consistency aped by only doing it on people with or with the named symptom. And the logic of each sentence making it n/a fit someone without it and must be ‘yes’ for those with it. It’s like a trick to confirm their groups.


if you had a bunch of healthy people who’d been made to do a five day army training their answers would be no different to those who had a serious illness. Because the only logical / makes sense answer from anyone exhausted is pre-determined as apparently meaning ‘catastrophisation’ when actually it’s ’what any normal person with a pain or exhaustion should logically answer’

if you artificially induce the same symptom in people who don’t have either the disease or any catastrophisation or mental health anything and they answer the same as those ill with those symptoms then what is it testing but that ‘induced’ or ‘real’ symptom and the logical answer related to the leading question.

 

[Sean]

It could also be argued that those diagnosing are in fact projecting their catastrophising onto those being diagnosed. They are catastrophising about others psycho-behavioural responses.

 

[Barry]

These scales have been used by the Chalders of the world to psycho-pathologize sick people. They tie it in with "fear avoidance" behavior, which to them represens "catastrophizing" rather than people having a realistic appraisal of their fatigue/pain symptoms and how they respond to activities.

Yep. If any of these folk suffered from, say a peanut allergy, they would experience a very rational fear causing them to avoid eating peanuts - fear doing exactly what nature intended. Fear avoidance behaviour seems very reasonable and sane to me. Why do these people brand it as a psychological fallibility? They seem to experience an irrational fear avoidance of common sense.

Edit, just to add: It's not about fear avoidance behaviour per se, but about whether that behaviour is rational or not. In many cases it is very rational, but these psychs like to brand it as if all such behaviour is irrational.

 

[Sean]

As I get older I find myself becoming more wary of heights with edges (cliffs, ladders, etc). It doesn't scare me, but the innate subconsciously sourced warning signs to keep a greater distance from the edges get stronger.

Psychopathologisers would say I am developing an irrational fear of heights.

I would say my body is behaving in a completely healthy common-sense protective way to allow for my reduced neuro-sensory-motor capacity that is normal with ageing, particularly in combination with having a disease known to affect such systems.

Injuries from falling off ladders is well known to be common for older men. That is, for the ones who don't pay attention to such normal healthy warning signs.

 

[Peter T]

As I get older I find myself becoming more wary of heights with edges (cliffs, ladders, etc). It doesn't scare me, but the innate subconsciously sourced warning signs to keep a greater distance from the edges get stronger.

Psychopathologisers would say I am developing an irrational fear of heights.

I would say my body is behaving in a completely healthy common-sense protective way to allow for my reduced neuro-sensory-motor capacity that is normal with ageing, particularly in combination with having a disease known to affect such systems.

Injuries from falling off ladders is well known to be common for older men. That is, for the ones who don't pay attention to such normal healthy warning signs.

It is interesting that I have the same experience. It is not that I am afraid of heights but that my body freezes. Several years ago I was at an art installation in Düsseldorf, where the Kunstgalerie was made up of two tall nineteenth century buildings joined by a three story glass atrium. The installation consisted of a net slung across the atrium just below the ceiling that people could access. With my eyes open I just froze at that height though I could move freely if I had my eyes shut or if I held someone else’s hand.

 

[Sean]

@Peter Trewhitt

Even from the safety of the couch in my ground level house I can't watch climbing videos any more, especially those solo free-form ones. I break out in a cold sweat and my stomach is doing somersaults.

Interestingly it doesn't happen if I am on plane at 20 000 feet and look out of the window.

 

[Barry]

I remember when I was much younger going to watch the film "Where Eagles Dare" when it first came out, in a fancy cinema that had a very wide screen, completely immersive. The opening scene is of a plane flying over mountains, and it suddenly flies over this huge valley - the sense of vertigo was very real for a moment. (But no fear avoidance behaviour ... I still stayed in my seat .)

 

[SNT Gatchaman]

Avindra Nath, being interviewed for the HealthRising blog —

"We hope that one of the major takeaways from our study is that we have convincingly demonstrated the biological basis of the disease that cannot be explained by deconditioning and psychological factors."



Paper says —

At maximal performance, a substantial group difference in cardiorespiratory capacity became apparent, which was related to both chronotropic incompetence and physical deconditioning.

With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. All these features make up the PI-ME/CFS phenotype.

 

[Haveyoutriedyoga]

Avindra Nath, being interviewed for the HealthRising blog —

"We hope that one of the major takeaways from our study is that we have convincingly demonstrated the biological basis of the disease that cannot be explained by deconditioning and psychological factors."



Paper says —

That seems contradictory, but is it that deconditioning only counts at max performance but max isn't what is most relevant when looking at MECFS?

 

[Arnie Pye]

A blog by Cort Johnson :

Title : The Exhausted Immune Cell Sweepstakes: Spanish Group Proposes Exhausted T-cells and Pituitary Damage are Driving ME/CFS

Link : https://www.healthrising.org/blog/2024/11/14/exhausted_immune-t-cells-chronic-fatigue-syndrome/

Mentions Avindra Nath, who is also mentioned in the previous two posts, so the blog is probably based on the interview mentioned above.

 

[Kitty]

That seems contradictory

Yep, it is. At black-is-white level.

is it that deconditioning only counts at max performance but max isn't what is most relevant when looking at MECFS?

I doubt it. Millions of people are deconditioned, yet they're healthy. Deconditioning's a result of ME/CFS, and it isn't a perpetuating factor.

That much is apparent because as soon as people with fluctuating ME/CFS find themselves with increased activity capacity, they make full use it. Many will get their fingers burnt at some point by being over-enthusiastic, and find themselves on a downward slope again. In other words, improving their fitness makes their ME/CFS worse.

 

[forestglip]

A sort of quick abstract if you don't want to read it all

I looked at red blood cell count, and it was positively correlated with brain fog in ME/CFS. High RBC might be a marker of low oxygen.

I then tested all blood markers. After multiple test correction, total bilirubin (pos), relative lymphocytes (neg), and relative neutrophils (pos) are (close to) significantly correlated with brain fog.

-----------------------------

Background for why I looked at this. Skip to past dividing line to see data.

This post gave me a bit of inspiration:

Researchers from the University of Iowa in Iowa City set out to assess associations between pulmonary MRI gas exchange, structural and functional brain MRI, and cognition in long COVID patients. In pulmonary gas exchange, oxygen moves from the lungs to the bloodstream, while carbon dioxide moves from the bloodstream to the lungs.

[...]

The results showed that lower pulmonary gas exchange may be associated with cognitive dysfunction

I've noticed on my own lab tests that only one test, red blood cell count, has been consistently near or slightly above the max of the reference range, at least in the last few years. Cleveland Clinic says the range is 4.5 to 6.1 for males, and mine have been between 5.7 and 6.5. Hematocrit and hemoglobin, less high, but still near the top of the reference range.



Not sure why it suddenly got high 3 years ago. I don't think my brain fog, or any other symptoms, significantly increased then. It could be that from 2019 to 2023, I was slowly tapering off of a medication, clozapine, which might align with the value increasing over that time. The reason I have a bajillion blood tests is because there's a risk of severely low neutrophil count with that medication, so they needed to monitor it. Now I'm off the med (and all other meds for most of the time since early 2023).

Cleveland Clinic and Wikipedia say one of the most common causes of high red blood cell count is low oxygen. Though my oxygen saturation is usually normal, around 98%. Sleep apnea can be a cause, and I did do a sleep lab a few months ago, which showed very mild sleep apnea. I have been using CPAP for a couple months, with no change in symptoms, and RBC was still high at the most recent two tests that were after over a month of use.

Polycythemia (also known as polycythaemia) is a laboratory finding in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

Secondary polycythemia is the most common cause of polycythemia. It occurs in reaction to chronically low oxygen levels, medications, other genetic mutations that impact the body's ability to transport or detect oxygen, or, rarely because of certain cancers.[4]

------------------------------------

So thinking RBC might be a marker of low oxygen, I was wondering if I could see a relationship between RBC and brain fog score in the NIH Deep Phenotyping data.

I looked at the "Brief Fatigue Inventory" and "Clinical Master Labs" datasets, found under "Post-Infectious MECFS at the NIH: Clinical Data Files" on mapmecfs.org.

The "Brief Fatigue Inventory" includes these items:

NIH_BFI_DIFFICULTY_CONCENTRATE
NIH_BFI_MOTIVATE_START_ACTIVITIES
NIH_BFI_FEEL_TENSE_PT
NIH_BFI_FEEL_TENSE_NURSE
NHL_BFI_FEEL_FATIGUE
NIH_BFI_DIFFICULTY_PERFORM_ACTIVITIES
NIH_BFI_HEAVINESS_LIMBS
NIH_BFI_SLOWNESS_THOUGHT_NURSE
NIH_BFI_SCORE [Combined sum of the rest of the scores]

The two that look relevant to brain fog:

NIH_BFI_DIFFICULTY_CONCENTRATE
Do you have difficulty concentrating or collecting your thoughts in the past week? 0 No Difficulty 1 2 Occasional Difficulty 3 4 Moderate Difficulty 5 6 Great Difficulty Examples of Follow-up Questions (as needed): How has your memory been this past week? Reading? Watching TV? Holding a conversation? Difficulty getting your thoughts started? How about making minor decisions? Have you been getting easily distracted?

NIH_BFI_SLOWNESS_THOUGHT_NURSE
Nurse Observation Only: slowness of thought and speech impaired ability to concentrate decreased motor activity? 0 Normal Speech And Thought 1 Some Slowness with Response 2 Obvious Slowness with Response 3 Interview Difficult 4 Complete Stupor

I added the two scores up into a "brain fog" score. This is for ME/CFS participants only. Looks like there might be a correlation with "RBC (M/mcL)". Pearson's r correlation is 0.46, p = 0.070.


They did another fatigue questionnaire, "Multidimensional Fatigue Inventory", which includes a "MENTAL_FATIGUE_SCALE" score that matches what I get from summing up these questions:

MFI_FOCUS_THOUGHTS: When I am doing something I can keep my thoughts on it
MFI_THOUGHTS_WANDER: My thoughts easily wander
MFI_EFFORT_CONCENTRATE: It takes a lot of effort to concentrate on things
MFI_CONCENTRATE: I can concentrate well

If I use that it's even more correlated with RBC count. r = 0.52, p = 0.032


And if I add the scores from both surveys together, it's even more correlated. r = 0.60, p = 0.013


I also tested correlations of every blood test they have with the combined brain fog score, and did Benjamini-Hochberg correction. Let me know if you can't see the data from embedding a Google Sheet, and I'll post it another way.


"Bilirubin Total (mg/dL)" (positively correlated) and "CD8/CD3 (#/mcL)" (negatively correlated) both have corrected p-values of 0.0604.

Edit: I added Spearman correlations in case some of the assumptions of Pearson are not met. Click the tab at the bottom of the spreadsheet above to switch to Spearman. Bilirubin still in the top spot, but now Lymphocytes (%) are negatively correlated and Neutrophil (%) positively correlated with brain fog with corrected p-values of 0.063.

Edit2: Plotted bilirubin to see what's so special. It does look like a strong correlation with brain fog.


Note: One participant was excluded for the bilirubin calculation because their lab value is "<0.2", which is not a specific number. Their brain fog score is 17. If I guess and say their bilirubin is 0.1 so that they are included, then it does decrease the correlation a bit:


Edit3: And here are lymphocytes and neutrophils:


Edit4: If including healthy participants, the correlation goes down for all the ones I plotted. For example, RBC and bilirubin (blue is healthy):


Edit5: And just a note about the MFI questionnaire, since I just noticed and was confused by why it seems to ask for a 1 to 5 score for opposite statements like "It takes a lot of effort to concentrate on things" and "I can concentrate well" and then adds them up. I found instructions for the MFI-20 which say the positively worded questions have to be reversed (so 5 becomes 1, etc). It seems they have done that with the mapmecfs data so the scores can be safely added.

 

[Turtle]

Background for why I looked at this. Skip to past dividing line to see data.

This post gave me a bit of inspiration:


I've noticed on my own lab tests that only one test, red blood cell count, has been consistently near or slightly above the max of the reference range, at least in the last few years. Cleveland Clinic says the range is 4.5 to 6.1 for males, and mine have been between 5.7 and 6.5. Hematocrit and hemoglobin, less high, but still near the top of the reference range.

Thanks again.
You are a whole lot more persistent than the 70 + NINDS group. Outperforming the researchers!!
And I like you're way of thinking here a lot!

 

[forestglip]

Edit: I added Spearman correlations in case some of the assumptions of Pearson are not met. Click the tab at the bottom of the spreadsheet above to switch to Spearman. Bilirubin still in the top spot, but now Lymphocytes (%) are negatively correlated and Neutrophil (%) positively correlated with brain fog with corrected p-values of 0.063.

So high relative neutrophils and low relative lymphocytes have the highest spearman correlations with brain fog.

(This is after adding in a guess for the missing participant's total bilirubin where it says "<0.2". Best case correlation for bilirubin is 0.67 if the real value is 0.2, worst case is 0.65 if the value is 0. Still high but neutrophils and lymphocytes are higher at -0.7 and 0.72.)

I searched Google Scholar, and apparently absolute neutrophil to lymphocyte ratio (NLR) has been found to be associated with cognitive dysfunction.

So first here's the data from the NIH study for NLR calculated from [Neutrophil Abs / Lymphocyte Abs] versus brain fog (calculated by summing relevant question scores in MFI and BFI questionnaires):

Spearman correlation = 0.707, p = 0.0022

And here is some of the literature:

Association between the neutrophil-to-lymphocyte ratio and cognitive impairment: a meta-analysis of observational studies, 2023, Hung et al

The neutrophil-to-lymphocyte ratio (NLR) has emerged as a preferred biomarker for assessing systemic inflammation owing to its novelty, cost-effectiveness, and suitability for extensive screening (23–25). Recently, several studies demonstrated a positive correlation between elevated NLR and cognitive impairment/mild cognitive impairment (26–28).

The analysis included four studies involving patients aged ≥ 60 years or older (26, 28, 30, 36), four studies involving patients with stroke (27, 29, 33, 35), two studies focused on patients with type 2 DM (32, 34), and one study involving patients with metabolic syndrome (31).

This meta-analysis included 11 studies published between 2018 and 2023, involving 10,357 patients. Pooled results revealed that patients with cognitive impairment had a higher NLR than those without cognitive impairment. From the nine studies that provided relevant data, a meta-analysis was conducted to estimate the pooled risk of cognitive impairment in patients with a high NLR, which showed a significant association (OR = 2.53). Our meta-regression indicates diabetes and hypertension, but not age, as significant moderating factors influencing the association between NLR and risk of cognitive impairment.

 

[forestglip]

Assuming NLR (neutrophil count / lymphocyte count) is actually related to cognitive impairment, I wonder if we can figure out which specific cognitive ability it best predicts.

The deep phenotyping study did an assortment of cognitive tests:

1. Wechsler Test of Adult Reading (WTAR) (The Psychological Corporation, 2001) requires the examinee to read words aloud.
   
   
2. Wechsler Adult Intelligence Scale – Fourth Edition (WAIS-IV) subtests including Coding, Symbol Search and Digit Span will be administered. For these subtests, examinees memorize strings of numbers or complete speeded tasks involving unfamiliar symbols.
   
   
3. Test of Variables of Attention requires examinees to rapidly respond using a button press to certain target stimuli and not distractor stimuli.
   
   
4. Hopkins Verbal Learning Test-Revised (HVLT-R) requires examinees to remember words that were read to them earlier.
   
   
5. Brief Visual Memory Test-Revised (BVMT-R) requires examinees to remember designs that were shown to them earlier.
   
   
6. Wisconsin Card Sort Test (WCST-64) requires examinees to utilize corrective feedback to learn how to sort cards.
   
   
7. Controlled Oral Word Association Test (COWAT; FAS and Animals) requires examinees to generate words to various cues.
   
   
8. Paced Auditory Serial Addition Test (PASAT) requires examinees to rapidly perform serial addition.
   
   
9. Grooved Pegboard Test requires examinees to rapidly insert pegs in holes.
   
   
10. Word Memory Test requires the examinee to view words and later remember them.
    
    
11. B Test asks the examinee to rapidly discriminate between letter stimuli.
    
    
12. Dot Counting Test asks the examinee to count dots as rapidly as possible.
    
    
13. Minnesota Multiphasic Personality Inventory – 2 Restructured Form (MPI2-RF) requires examinees to complete true-false items that best describes themselves.

Here are the correlations of each neurocognitive test with NLR:


It looks like these three are the highest correlated to NLR using either Pearson or Spearman:

• Test of Variables of Attention requires examinees to rapidly respond using a button press to certain target stimuli and not distractor stimuli.
• Paced Auditory Serial Addition Test (PASAT) requires examinees to rapidly perform serial addition.
  
• WAIS IV - Digit Span:

This test has three parts:
■ Digit Span Forward (individual tries to repeat digits forward)
■ Digit Span Backward (individual tries to repeat digits backward)
■ Digit Span Sequencing (individual tries to repeat digits in ascending order)

While NLR is not very correlated to these tasks:

• Grooved Pegboard Test requires examinees to rapidly insert pegs in holes.
• Brief Visual Memory Test-Revised (BVMT-R) requires examinees to remember designs that were shown to them earlier.
• WAIS IV - Symbol Search:

The client, under time pressure, scans a search group and indicates whether one of the symbols in the target group matches. This test measures:
■ processing speed
■ working memory with visual stimuli

It looks like it mainly correlates to tasks requiring focus/attention, and not so much for tasks requiring memory, processing speed, or dexterity.

--------

Edit: The above correlations are only using ME/CFS participants. If I add the healthy participants, it more or less replicates my results. The regression line for digit span is very similar between groups:


The other two most correlated ones are pretty similar as well:


While these tests which were not very correlated, are not similar in the healthy group:


Edit 2: So what I would tentatively conclude is that neutrophil to lymphocyte ratio (NLR) may be associated with cognitive impairment, not only in the general population, but also in ME/CFS. In ME/CFS, the relationship is most apparent for subjective mental fatigue, but maybe also on tasks like digit span. It'd probably be good to watch the research on NLR's relation to cognitive impairment.

 

[Dolphin]

ME – An Immune, Autonomic Nervous System, Brain & Gut Disease: A Talk with Dr Avindra Nath & Dr Vicky Whittemore by Bronc

https://forums.phoenixrising.me/thr...vicky-whittemore-by-bronc.92894/#post-2470269

https://twitter.com/user/status/1868045388462399774

 

[forestglip]

Edit: No need to read this post. Just me figuring out the data said cells/ul, but they meant cells/mL. Only leaving it up in case someone else is confused about the high numbers.

-------------

Am I missing something? Supplementary file 15 (requires downloading and unzipping) has a section for "Supplementary Data 15C: Flow cytometry of cerebrospinal fluid to assess cell type proportion". In this section there is a row for "Lymphocyte CD4+ T cell (cells/ul)". The numbers seem pretty extreme.

For healthy volunteers the median CD4 cell count per microliter was 656.35.

I found a study that looked at lymphocyte counts in CSF in "84 individuals without neurological disease who underwent spinal anaesthesia for surgery". Median CD4+ count/uL in these people was 0.44 (0.08–1.43). 650 is much higher than 0.44.

Other lymphocyte counts seem higher than they should be too. I didn't list all of the abnormal values.

Medians for HV in deep phenotyping study:
Monocytes - 48 cells/uL
NK cells - 34 cells/uL
CD8+ T cells - 166 cells/uL

Medians from the lymphocyte study I linked (range given from 5th to 95th percentile):
Monocytes - 0.23 (0.08–1.11) cells/uL
NK cells - 0.01 (0.00–0.05) cells/uL
CD8+ T cells - 0.13 (0.04–0.40) cells/uL

Edit: Changed to median calculation in deep phenotyping study to match other study.

 

[forestglip]

Edit: See post #873 for the finished version of the spreadsheet.

-------

I thought it could be useful to create a dataset showing how much every single test from the deep phenotyping study is correlated to ME/CFS severity.

I combined all data files into one which yielded about 3000 tests. These include lab tests and questionnaires.

For an ME/CFS severity metric, this was kind of an arbitrary choice. I decided to add together all the scores from the Multidimensional Fatigue Inventory (MFI) and the Multiple Ability Self-Report Questionnaire (MASQ). These two surveys basically cover mental and physical fatigue. Here are the descriptions from mapmecfs:

Multidimensional Fatigue Inventory (MFI)
The Multidimensional Fatigue Inventory (MFI) is a validated 20-item self-report instrument designed to measure fatigue severity. The items are designed to assess general, physical, emotional, and mental manifestations of fatigue as well as vigor, an estimate of the patient’s energy level. The MFI-20 has been validated in chronic fatigue syndrome patients. This questionnaire is part of the PI-ME/CFS research definition

Multiple Ability Self-Report Questionnaire (MASQ)
The Multiple Ability Self-Report Questionnaire (MASQ) is a 38-item questionnaire that assesses the subjective appraisal of cognitive difficulties in five cognitive domains: language, visual-perceptual ability, verbal memory, visual- spatial memory, and attention/concentration. The MASQ sub-scales are scored on an 8–40 point scale with high scores indicating greater perceived difficulties

I tested Spearman correlation between each of the ~3200 tests and this severity metric, and here are the results in a spreadsheet. The more red, the more of a positive relationship between the test and fatigue severity. The more blue, the more negative. These are sorted by p values.

I only tested ME/CFS participants.

I've added a few miscellaneous notes on the second tab of the spreadsheet. I uploaded the spreadsheet as a file as well because this widget can't be zoomed or rearranged.

(Edit: Here's a link to the browser version.)


I think this could highlight useful things to look at if they are highly correlated with severity. But also, it makes it easy to quickly compare the results of other studies to see if the NIH study found something similar or not.

Again, my choice of metrics for severity was pretty arbitrary. I had made one I liked more by using those two I listed, plus CDC Symptom Inventory (CDC-SI), which is over 100 questions, but many weren't answered by everyone, so i had to manually find all the ones that were. I normalized the scores of all three surveys, then added them together. But the calculations in the spreadsheet got so complicated I couldn't be sure I hadn't made a mistake somewhere, so I went with something simpler for now.

But if anyone has suggestions for a better metric for severity, I think these are all the subjective questionnaires:

Brief Fatigue Inventory (NIH-BFI)
The National Institutes of Health – Brief Fatigue Inventory (NIH-BFI) is a 7-item clinician-administered questionnaire. To assess reliability, a principle component analysis was applied and yielded a single component. Further, the NIH-BFI produced Cronbach alphas ranging from .81 - .88. The NIH-BFI is strongly correlated with fatigue items from validated clinician-administered depression and mania scales.

Fatigue Catastrophizing Scale (FCS)
The Fatigue Catastrophizing Scale (FCS) is a 10-item paper/pencil questionnaire to measure catastrophizing related to the fatigue experience. This questionnaire takes less than two minutes to complete. It uses a 5-point rating scale (1= never true) to (5= all the time true) with proven high internal consistency reliability (coefficient alpha = 0.85 – 0.92).

Gratitude Questionnaire
The Gratitude Questionnaire is a six-item self-report questionnaire designed to assess individual differences in the proneness to experience gratitude in daily life. The gratitude questionnaire was only administered to the ME/CFS participants.

McGill Pain Questionnaire (MPQ)
The McGill Pain Questionnaire (MPQ) is a list of 20 groups of adjectives to describe sensory, affective and evaluative aspects of pain.

Multidimensional Fatigue Inventory (MFI)
The Multidimensional Fatigue Inventory (MFI) is a validated 20-item self-report instrument designed to measure fatigue severity. The items are designed to assess general, physical, emotional, and mental manifestations of fatigue as well as vigor, an estimate of the patient’s energy level. The MFI-20 has been validated in chronic fatigue syndrome patients. This questionnaire is part of the PI-ME/CFS research definition

Multiple Ability Self-Report Questionnaire (MASQ)
The Multiple Ability Self-Report Questionnaire (MASQ) is a 38-item questionnaire that assesses the subjective appraisal of cognitive difficulties in five cognitive domains: language, visual-perceptual ability, verbal memory, visual- spatial memory, and attention/concentration. The MASQ sub-scales are scored on an 8–40 point scale with high scores indicating greater perceived difficulties

Beliefs About Emotions
The Belief About Emotions scale is a validated questionnaire designed to measure the beliefs of expressing negative thoughts and feelings.

Neuropathic Pain Scale (NPS)
The Neuropathic Pain Scale (NPS) is a questionnaire designed to assess distinct qualities associated with neuropathic pain. It measures both the quality and the intensity of the neuropathic sensations.

Patient Health Questionnaire-15 (PHQ-15)
The Patient Health Questionnaire-15 (PHQ-15) is a validated questionnaire used to assess somatic symptom severity and the potential presence of somatization and somatoform disorders.

Pittsburgh Sleep Quality Index (PSQI)
The Pittsburgh Sleep Quality Index (PSQI) measures sleep quality over a 1-month period with 19 questions in 7 clinically-derived component scores. This instrument has a sensitivity of 89.6% and a specificity of 86.5% for identifying a sleep disorder (PSQI<5) in a clinical sample.

Short-Form 36 (SF-36)
The Short-Form 36 (SF-36) is easily administered and reliably reflects health-related quality of life outcomes. This questionnaire has 36-items that assess eight health issues: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, general mental health, social functioning, energy/fatigue, and general health perceptions. The SF-36 has been tested and validated extensively in a number of clinical populations and was developed for self- administration by patients. This questionnaire is part of the PI-ME/CFS research definition.

CDC Symptom Inventory (CDC-SI)
The CDC-SI is used to collect information on occurrence, frequency, and intensity of symptoms common in ME/CFS and other fatiguing illnesses.

Polysymptomatic Distress Scale (PSD)
The Polysymptomatic Distress Scale (PSD) is a self-administered instrument that determines both the distribution of painful areas across the body and an estimate of related symptom burden. Evidence supports the reliability and validity of the PSD in the general population.

PROMIS: Emotional Distress – Anxiety
PROMIS: Emotional Distress – Depression
PROMIS: Fatigue
PROMIS: Global Health
PROMIS: Pain – Behavior
PROMIS: Pain Intensity
PROMIS: Pain – Interference
PROMIS: Sleep Disturbance
PROMIS: Sleep-Related Impairment
Patient Reported Outcomes Measurement Information System – Short Forms (PROMIS-SF) is a system of highly reliable, precise measures of patient–reported health status for physical, mental, and social wellbeing. These computer adaptive tests are generally less than 6 questions and developed from more than 1000 datasets from multiple disease populations including cancer, heart disease, rheumatoid and osteoarthritis, psychiatric conditions, spinal cord injury, and chronic obstructive pulmonary disease. Initial psychometric properties showed internal consistency reliability coefficient of 0.81. PROMIS-SF include Fatigue, Pain Behavior, Pain Interference, Pain Intensity, Global Health, Emotional Distress – Anxiety, Emotional Distress- Depression, Sleep-Related Impairment and Sleep Disturbances.

Beck Depression Inventory-II (BDI-II)
The Beck Depression Inventory-II (BDI-II) is a 21-question validated self-report inventory for measuring the severity of depression.

Beck Anxiety Inventory (BAI)
The Beck Anxiety Inventory (BAI) is a 21-question validated self-report inventory for measuring the severity of anxiety.

Center for Epidemiologic Studies Depression Scale – Revised (CESD-R)
The Center for Epidemiologic Studies Depression Scale – Revised (CESD-R) is a 20-item validated self-report inventory for screening for depression.

Post-traumatic Stress Diagnostic Scale (PDS)
The Post-traumatic Stress Diagnostic Scale (PDS) is a validated instrument for the epidemiologic diagnosis of Post-traumatic Stress Disorder.

RN Polysymptom Index
Measures of subjective symptoms collected during a structure interview

Thanks mapmecfs:

1. Walitt, B., et al. “Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Nature Communications. February 21, 2024. DOI: 10.1038/s41467-024-45107-3
   
   
2. Mathur, R.* & Carnes, M.U.*, et al. mapMECFS: a portal to enhance data discovery across biological disciplines and collaborative sites. J Transl Med 19, 461 (2021). https://doi.org/10.1186/s12967-021-03127-3