The Netherlands - €28.5 million ME/CFS research program - ZonMW funding awards announced April 2023

Probably because that's writing down a lie and that's rarely a good idea:

Not ambiguous enough to pass the laugh test. It's not good when you can expect some litigious response and you just write down a bold lie.

 

I feel the strategy here and in other places where we're fighting for our rights the strategy is simply to let us tire. @Arvo has put in an enormous amount of effort detailing the problems here. Dutch people with ME have been active and we've been getting some help from abroad too. This however does have the distinct feeling of letting us tire ourselves out, ride out the storm and then do whatever you want anyway.

I doubt it's gonna work that way this time around. Sincerely hope not.

 

I've been collecting the ways ME/CFS Lines doesn't adhere to the ZonMw Research Program ME/CFS.

I wanted to put a spot on two additional things in this thread.

1) the obscuring of which criteria they use in Lifelines and its sub-project ME/CFS Lines: it's really not an accident but set up in a way that would probably make them use plausible deniability if it got called out.

Check out the Lifelines wiki page for "fatigue (CDC)", their newly created page that is supposed to be about documenting CFS. (All CFS related pages in Lifelines can be found here.)
It is truly misleading:


The title is "fatigue (CDC)" and the first sentence is: “The Centers for Disease Control and Prevention (CDC) symptom inventory for chronic fatigue syndrome (CFS or ME) is aimed to assess whether a person meets the CDC diagnostic criteria for (CFS)1) (section: diseases & symptoms).”

• "Centers for Disease Control and Prevention (CDC)" links to the current CDC info on ME, that uses the IOM criteria
• "chronic fatigue syndrome" links to wikipedia, that talks about "the CDC's diagnostic criteria" when meaning the IOM criteria, and also states:

“Distinguishing core symptoms are lengthy exacerbations or flare-ups of the illness following ordinary minor physical or mental activity, known as post-exertional malaise, greatly diminished capacity to accomplish tasks that were routine before the illness; and sleep disturbances. The Center for Disease Control and Prevention’s (CDC) diagnostic criteria also require at least one of the following: (1) Orthostatic intolerance (difficulty sitting and standing upright) or (2) impaired memory or attention.” ​

So title, and the first two links give the impression that Lifelines is using the same criteria as the CDC currently uses, the IOM.

This is exarcebated because nowehere on this page is there a link to the actual Fukuda criteria or a notification that that is what they are actually using.

Even reference 1, that should be referring to "the CDC diagnostic criteria" isn't actually about the CDC criteria at all, but links to an article by Bleijenberg (of course) about how there's a supposed overlap in (unhealthy) lifestyle facors between people with short term fatigue, chronic fatigue and people with "CFS-like fatigue (in accordance with the Center for Disease Control criteria for CFS, without clinical confirmation)". "For reasons of convenience, the term ‘CFS’ is used to describe the results of this study, although CFS was not medically confirmed."



In the available attachment from ME/CFS Lines' grant request something similar hapens, it says things like: "2,500 participants fulfilling CDC criteria" and "Genetic data will be collected in all participants fulfilling the CDC criteria" while, at least on that page, there is no mention or reference made to the fact that they mean Fukuda.

The ZonMw ME/CFS Lifelines info says: "In 2018, 2,500 Lifelines participants met CDC criteria for ME/CFS."


This is a recurring pattern, no accident, although of course when confronted they would probably say it was never a secret. (You have to look pretty hard though to find it, and I think people outside ME/CFS and low-informed patients will not recognise it.

 

Are they collecting data on who has PEM? If not, they cannot draw conclusions on ME/CFS as defined by the IOM.

We've seen a number of studies that drew conclusions about IOM ME/CFS without having any real data on PEM in the participants.

 

And 2)

Lifelines uses (at least theoretically, no idea how regular they were sent given patient reports) two questionnaires to diagnose "CFS":

• A Dutch version of the CDC symptom inventory, as "The CDC symptom survey improves the identification of participants that meet the diagnostic criteria for CFS/ME by assessing the presence of individual symptoms rather than the disease itself", and
• The CIS, based on Bleijenberg and Vercoulen, a psychosomatic questionnaire: "The questionnaire has been translated into multiple languages and is used to set diagnostic criteria for various illnesses, including chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS)". (again, see pages here)

I came across this study by Rosmalen, Knoop, Vercoulen & co, that uses Lifelines data to analyse "fatigue" in 23 chronic illnesses. (S4ME thread here.)

It says: "Chronic fatigue was defned as severe fatigue (CIS-Fatigue score≥35 points) lasting at least 6 months according to self-report."

So first of all Lifelines is using the CIS both to diagnose "ME/CFS" ànd to determine "chronic fatigue" in other chronic illnesses.

But also fatigue severity and duration are two out of three requirements for the CFS diagnostic score of Lifelines. If people in these chonic illnesses have for example a regular headache + sleep poorly + forgetful+aches in joints or throat, how well are these people separated from having ME/CFS if they aren't diagnosed properly?


(It illustrates again how important it is to use proper ME/CFS criteria based on a combination of PEM+cognitive dysfunction (not mere forgetfulness)+a form of dysautomnia).

 

No. Until September 2020 "CFS" was part of "fatigue (general)", and is after creating a new page for it still referred to as "fatigue (CDC)".

PEM also cannot be found in the Lifelines wiki. Looking at the "fatigue (CDC) page" they ask :
"worsening of complaints after physical activity / how often did you have the complaints listed below in the past 6 months?", and
"worsening of complaints after physical activity / have you had these complaints for more than or less than 6 months?"

which would be insufficient to ask after PEM.
But even if they would ask after it properly (which they don't as it's a psychosomatic project: it's led by Rosmalen, uses fatigue as its defining and only necessary symptom, uses psychosomatic questionnaires and references etc.), then it would still be insufficient as it's only optional. The ZonMw Research Programme ME/CFS requires the use of criteria that have PEM as a key symptom, and alignment with current international scientific development and biomedical projects, which again requires PEM.

 

I'm really starting to get uneasy about the whole Lifelines project, or at least Rosmalen's activities in it. I may be mistaken (my brain is mush atm), but it looks a lot like Lifelines is collecting all kinds of data about psychology, lifestyle, work, social circumstances etc., and then uses this data (or farms it out to other users) to create bps papers, connecting physical illness to psychological and sociological factors like they are of key influence. At least Rosmalen seems in the business of doing this.
(Like "Predictors of new onsets of irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia: the lifelines study" by Rosmalen I just posted about here.)

It would be a really sneaky way to propagate a psychosomatic (bps) approach within healthcare, following the goals of the European Association of Psychosomatic Medicine, that Rosmalen is vice president of (and Sharpe president).

Lifelines participants agreed to fill in questionnaires about their health and life for the greater good of datacollection on health & sickness, but I doubt that for example the participants with the 23 chronic illnesses in post #266 would have signed up for getting their illness bps-ed and assessed with a Bleijenberg questionnaire, looking for "fatigue", by someone who works closely with Knoop (who wants to expand CBT use to all illnesses and says behaviour is the main determining issue in sickness, more so than pathology) and Sharpe (with similar beliefs).

 

Just wanted to offer some moral support.

Too ill to follow this thread in detail but even on a cursory skim it looks like this is an issue which could have large ramifications for all of us, not just pwME in the Netherlands.

A truly mammoth effort by @Arvo (and undoubtedly others I'm not aware of) to obtain and collate all this information and to expose it to some much needed public scrutiny.

Thanks for all your work on this and fingers and toes crossed it'll lead to improved research quality.

 

Thank you @Ravn , and also @Solstice in an earlier post.

I don't know if it will make a difference, but I hope it will give international onlookers better access to what the ME/CFS Lines project is, instead of having to make do with what it pretends to be.

 

Hi,

Just coming here to thank everyone for their hard work unpacking this, especially to @Arvo for digging so deep.

Also, a heads-up to anyone who still thinks about sending an official complaint to ZonMw (the funding organisation). I understand it would need to be received (in paper form) before the 5th of June in order to be considered.
(That is assuming they will accept complaints made up to six weeks after the public announcement of the grants, rather than - as they have maintained - six weeks after the grant decisions were taken in February.)

A template letter from ME Centraal can still be downloaded at the following link (clicking on it will download the Word-file to your computer): https://mecentraal.files.wordpress.com/2023/05/zonmw-bezwaarschrift-mei-2023-3.docx

With permission from the writer I attach a complaint that was submitted this week. (It's in Dutch. I don't know whether I'll be able to make a translation - it's a long document.) It uses a lot of the arguments that @Arvo has provided in this thread and - on pages 3 and 4 - looks at the Lifelines Wiki in detail. Again, many thanks to @Arvo, Rob Wijbenga and anyone who is working hard to overturn this decision.

Now just hoping something will move at ZonMw.

 

Trying to pull together some of the things I have learned about the claims made by ME/CFS Lines regarding their cohort and how they could (potentially) be unpicked by mining the information on Lifelines Wiki. (With, again, many thanks to @Arvo).

First, here's the current project page on the ZonMw (the funding organisation) website:
https://projecten.zonmw.nl/nl/proje...biobank-unravelling-mecfs-aetiology-lifelines (Dutch)
https://projecten-zonmw-nl.translat...felines?_x_tr_sl=auto&_x_tr_tl=en&_x_tr_hl=en (machine translation)

Note the following quotes:
"The goal of ME/CFS Lines is to establish a multidisciplinary research infrastructure and build a longitudinal ME/CFS patient cohort and biobank based on the existing Lifelines population cohort. Diagnostic criteria for ME/CFS have been included in this cohort since 2014."
"Lifelines is the only population cohort and biobank worldwide to map diagnostic criteria for ME/CFS. In 2018, 2,500 Lifelines participants met CDC criteria for ME/CFS. Since then there have been at least another 400 people who have developed ME/CFS within the Lifelines cohort."


The following pages of Lifelines-Wiki seem relevant when asking how Lifelines determines CFS-status to participants:

1) Fatigue (general)
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_general
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_general&do=revisions

2) Fatigue (PROMIS <18)
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_promis_18
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_promis_18&do=revisions
(Note: 'PROMIS' stands for 'Patient Reported Outcomes Measurement Information System')

3) General health (PROMIS)
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=general_health_promis
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=general_health_promis&do=revisions
(Note: 'PROMIS' stands for 'Patient Reported Outcomes Measurement Information System')

4) Familial Chronic Fatigue Syndrome
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=familial_chronic_fatigue_syndrome
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=familial_chronic_fatigue_syndrome&do=revisions

5) Fatigue (CIS)
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_cis
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_cis&do=revisions
(Note: 'CIS' stands for 'Checklist Individual Strength')

6) Fatigue (CDC)
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_cdc
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_cdc&do=revisions

7) Chronic Fatigue Syndrome (CFS) Diagnostic Score
current page: https://wiki-lifelines.web.rug.nl/doku.php?id=cfs_diagnostic_score&s[]=fatigue
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=cfs_diagnostic_score&do=revisions

8) Overview changed variable names (potentially relevant)
current page: https://wiki-lifelines.web.rug.nl/d...e_names&s[]=cdc&s[]=complaints&s[]=adu&s[]=09
overview of revisions: https://wiki-lifelines.web.rug.nl/doku.php?id=changed_variable_names&do=revisions


Just fried my brain pasting this overview together, so will have to continue later.

 

Addressing those pages and instruments one by one.

1) Fatigue (general)
Asks questions about tiredness, fatigue, and exhaustion, their effect on functioning, duration of the symptom, and also elicits self-report of CFS, if applicable.
(Note: The Fatigue (CDC) page (more on that later) states: "Lifelines repeatedly assessed the presence of CFS/ME by self-report. However, recent studies indicate that this method misses ~90% of the CFS diagnoses. The CDC symptom survey improves the identification of participants that meet the diagnostic criteria for CFS/ME by assessing the presence of individual symptoms rather than the disease itself." 'Self-report' is a hyperlink in that quote and links to the 'Fatigue (general)' page, indicating that this is the instrument that provided those self-reports of CFS.)


2) Fatigue (PROMIS <18)
Asks parents questions about tiredness and weakness in their children and effect of these symptoms on functioning.
Asks adolescent participants those same questions about themselves.


3) General Health (PROMIS)
"[...] is a collection of seven short forms measuring the following seven domains of self-reported health in 4 items each:

1. depression
2. anxiety
3. physical function
4. pain interference (including a 5th item on pain intensity)
5. fatigue
6. sleep disturbance
7. satisfaction with participation in social role

Asks four (!) questions about fatigue (presence of fatigue in last seven days, how tired on average, difficulties starting things because of tiredness, how worn out did you feel on average). Also asks four questions about sleep (quality of sleep, how refreshing, presence of a sleep disorder, difficulty falling asleep).


4) Familial Chronic Fatigue Syndrome
Asks for presence of Chronic Fatigue Syndrome in participant's parents, children and siblings.


5) Fatigue (CIS)
"The Checklist Individual Strength (CIS) is a 20-item fatigue questionnaire developed in Dutch (section: diseases & symptoms). The questionnaire has been translated into multiple languages and is used to set diagnostic criteria for various illnesses, including chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS)."
Difficult to summarise the twenty questions here. I suggest you take a look (questions are provided in English translation).
But note:
"De CIS consists of 20 statements on fatigue-related problems respondents might have experienced in the past 2 weeks."
"A factor analysis indicated 4 components in the 20 questions:

• Subjective fatigue (8 items)
• Concentration (5 items)
• Motivation (4 items)
• Physical activity (3 items)"

I wonder: If this questionnaire asks questions about fatigue-related problems in the past two weeks, how is it used to "set diagnostic criteria for various illnesses, including chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS)"? I admit I don't even quite know what that last phrase means.


6) Fatigue (CDC)
Page has this to say: "The CDC symptom survey was developed in English and translated in Dutch.
The CDC symptom survey as used in Lifelines assesses 8 symptoms that are part of the diagnostic criteria for CSF, plus a question regarding depressive feelings in the last 6 months to increase the diagnostic value."
The questions asked concern frequency and duration of forgetfulness, problems concentrating, sore throat, tender neck or axillary nodes, sore muscles, painful joints, headache, waking up not feeling rested, worsening of complaints after physical activity, depressed feelings.

As @Arvo has noted elsewhere in this thread, the page 'Fatigue (CDC)' was only created on 29 September 2020 – after the first ZonMw work session for researchers, after completion of the draft version of the research agenda and during the period in which the draft of the research agenda was shared with researchers in the Netherlands for feedback.

While this certainly suggests opportunism (creating dedicated pages for CFS just as demonstrating expertise in this area becomes important for a grant application in the near future), does it mean 'Fatigue (CDC)' was not assessed in Lifelines participants before September 2020? Does it somehow falsify the claim that Lifelines knew it had 2500 participants fulfilling the Fukuda criteria in 2018?

Note that the question/variable tables on Lifeline Wiki contain a column 'Assessment' which lists the assessment rounds in which those questions were asked.
Consulting the variable table on the 'Fatigue (CDC)' page shows that all questions pertaining to 'Fatigue (CDC)' were first asked in assessment 2A, which (according to https://wiki-lifelines.web.rug.nl/doku.php?id=2a) "is the second general assessment of Lifelines." An overview page for the general assessments (https://wiki-lifelines.web.rug.nl/doku.php?id=general_assessments) lists 2A as: "Second assessment with questionnaires, measurements, and biosamples (2014-2017)".

So the questions used by Lifelines to determine 'Fatigue (CDC)' status of participants were indeed asked since 2014.

I was wondering whether the fact that the 'Fatigue (CDC)' page was created so late might mean that Lifelines had made no conscious attempt to assess 'Fatigue (CDC)' in its participants prior to 2020, then in 2020 pulled together, on that newly created 'Fatigue (CDC)' page, questions that happened to figure on some of their questionnaires and that were conveniently relevant to fullfilling Fukuda criteria.

This does not seem to be the case. Note that the variable codes on the 'Fatigue (CDC)' page all contain 'cdc'. For example, the code for the first question about forgetfulness is "cdc_forgetful_adu_q_01". And the table of changed variable names at https://wiki-lifelines.web.rug.nl/doku.php?id=changed_variable_names does not indicate that any variables that now contain "cdc" in their code previously didn't.
What this seems to indicate to me is that the questions listed on the 'Fatigue (CDC)' page did enter Lifelines as a conscious attempt to assess 'Fukuda CFS' in Lifelines participants.

To be continued.

 

Some more remarks regarding the 'Fatigue (CDC)' page...

The page states "The CDC symptom survey as used in Lifelines assesses 8 symptoms that are part of the diagnostic criteria for CSF [...]."
'As used in Lifelines' suggests that they may have created their own short form of the CDC symptom survey.
I would like to know more about how their set of twenty questions relates to the full Centers for Disease Control and Prevention (CDC) symptom inventory for Chronic Fatigue Syndrome and to existing short forms of it.
If anyone were up to looking into that, I think it would be worthwhile.

Even though the information in my last post above makes it clear that the claim "Diagnostic criteria for ME/CFS have been included in this cohort since 2014." is true in some sense, it remains a scandal (to my mind) that ME/CFS Lines has received funding and that those 2900 participants who fulfill Fukuda criteria (as far as one can tell from twenty answers on a questionnaire) are now considered an ME/CFS cohort fit for biomedical research.

I wanted to address further Lifeline Wiki pages, but really have to stop for today.

 

Decided to email Judith Rosmalen (29 May) [Note 1] & post that fact on Twitter [Note 2] limits deniability ---

Note 1
"Hi Judith,
I'm emailing you re ZonMW GWAS project which I understand is led by Cindy Boer. Cindy Tweeted "That would be my project . If you want, I do not mind walking you though details of my project - For example, I will work together with DecodeME, - or answering questions about it. send me a message." [Note 1]

I've replied to Cindy's Tweet [Note 2 & 3] but I have't had a reply - perhaps you could provide details of the GWAS or forward this to Cindy for her to reply?
1) total number of participants i.e. GWAS?
2) Cindy stated "I will work together with DecodeME" - typically GWAS studies need to be combined i.e. to generate sufficient data to identify relevant genes. Will the selection criteria used enable all/part of your data to be combined with DecodeME data? If only part of the ZonMW GWAS data will match the criteria used for DecodeME then can you estimate the %?

Thanks in advance,"
Note 2
Tweet
Proinsias Ó Martain
@FMM0179
·

No reply - to my replies above emailed [j.g.m.rosmalen@umcg.nl] ZonMW project lead with same questions on 29 May. "1) total number of participants i.e. GWAS? 2) selection criteria --enable --data to be combined with DecodeME data? -- only part of the ZonMW GWAS data will match?

 

Folks I've just received a response to my email here it is --- not sure whether the Dutch/ZonMW data [will be comparable to/can be combined with] the UK (DecodeME) data so I'm posting it here i.e. to get your views!
@Andy

"
Dear Francis,


You had some questions regarding my project studying the genetic background of ME/CFS. see below for my reply

1. Total number of participants i.e GWAS?

The project consists out of a world-wide GWAS meta-analysis, meaning every study participating (biobank, dataset, patient population etc) will perform the same GWAS and share the results with me, which will then be Meta-analysed. For this to be reliable and robust large sample sizes are needed (hence the world-wide collaboration) and from our power calculation, also part of our application, and genetic datasets available world-wide we calculated a sample size of 22.000- 42.000 cases.

1. Collaboration with DecodeME and data combination

As stated above, only results level data will be combined, this is the validated and standard practice in GWAS meta-analysis, there are set protocols for this that need to be followed. The benefit of this is that results form GWAS meta-analysis are very robust and reliable.



From your message, however, I gather your questions relate not so much to sample size of specific GWAS methodology, but I suspect, your questions are more regarding the case definitions. I can assure you that my analysis plan has been examined and approved by multiple patients, ME/CFS experts, ME/CFS clinicians both national and international. I am a genetics and GWAS expert, I have worked in the GWAS field successfully for 10 years, I have studied multiple different subjects (predominantly osteoarthritis and (chronic) pain) which includes also complex phenotypes with multiple definitions/ways to measure. I am well aware of the problems regarding ME/CFS case criteria and all of the different criteria that exist. This is why my analysis plan contains state-of-the-art methods, multiple analysis and individual criteria specific sensitivity analysis in order to correctly analyse and define patients.



I hold my work to very high standards, and this project will be no different.



regards,



Dr. Cindy G. Boer

Postdoctoral researcher

Department of Internal Medicine

 

To repeat what has been said already, for the most accurate results from any meta analysis then the inclusion criteria that the data is based on needs to be the same.

DecodeME has used the IOM/NAM and CCC, and there is nothing there to confirm what criteria the Lifeline's cohort will use, so if it is different to DecodeME and both cohorts are used in this planned meta analysis then that would decrease the confidence in the results of the meta analysis.

 

Given the history of ME, this person should know how laughable this statement is without names and visibility into their work. Even more so with what we've seen of this cohort and who leads it. It would take strong assurances from the DecodeME team to trust this.

We've seen the standards from this cohort and Rosmalen's work, they're not much to look at.

 

Thanks. I appreciate that this is technical and my understanding is limited, but yes --- if straightforward reassurance could be given --- then why not give it --- DecodeME has used the IOM/NAM and CCC, and ZonMW will ---- use the same criteria --- therefore, in simple terms, the data can be
combined.
Obviously there are reason's for the weasel words --- good to see that undergraduate/postgraduate education hasn't been wasted ---

 

It's an empty/hollow letter, especially regarding the criteria.

It does not give a practical, specific answer, but uses non-specific language while making appeals to authority and accomplishment to deflect from not being transparent or following research program requirements.

Also, I find the "It's fine because unspecified "authorities" said so and anyway I'm a Scientist and I know what I'm talking about" as an answer to an informed patient inquiring about the specifics of the study she intends to do using that patient's disease to further her career and income quite insulting actually. It's not only insufficient, but also patronising. Btw., those "experts" and "clinicians" could easily be Rosmalen, Knoop and their associates as that's her circle atm., but even if it were Scheibogen, Davis and Systrom it still would not matter as the way Lifelines assesses and selects patients is not according to the Research Program & grant requirement which specify that the study uses criteria that have PEM as mandatory symptom and aligns with current international scientific standards for ME/CFS research and international similar projects, and doing a GWAS on a Lifelines cohort and divide patients according to several criteria sets afterwards isn't that.

Notice how she does not say that she is following the requirements of the Research Program and uses CCC, ICC or IOM criteria. Nor does she say "Yeah, Lifelines was insufficient, but we filter out proper participants fitting ICC/CCC/IOM criteria by questionnaire and then give that group a clinical assessment to confirm the diagnosis."

Also notice how her last two lines are a new way of saying that they are indeed doing what was said several times before: that they are going to do an inter-criteria analysis afterwards based on the Lifelines cohort (self-reported, non-clinical, partially LL-diagnosed by questionnaires that ask after fatigue not ME/CFS, based on CDC'94). No-one asked for that, the Program's goal is to do biomedical research which practically helps patients; it also specifically states that criteria might change soon due to research finds.

Together with what she said about her study earlier (which can be found here) I am rather disappointed in dr Boer, despite her promising cv.