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

Yes! That statement is in the explainer box attached to the diagram I just posted above. That diagram and that explainer will be used in exactly that way, creating wiggle room for use of Fukuda.
If anyone has read the Jason study the diagram is from (or based on), I'd be interested to know how this view of how the criteria populations relate to each other is justified or arrived at there.

 

The reason ICC, CCC and IOM criteria were specified is almost certainly to ensure that Fukuda criteria would not be used.

 

The explainer box attached to that diagram reads as follows (the crucial sentence was already highlighted by @Medfeb above):

Dutch:

Spoiler: Explainer box in Dutch

"Figuur 1: Vergelijking van verschillende criteriasets voor ME/CVS naar aantallen patiënten.
De International Concensus Criteria voor ME (ME-ICC) uit 2011 vormen de meest recente en stringente beschrijving van ME/CVS; patiënten die voldoen aan deze set criteria kunnen op dit moment als kern van de ME/CVS-populatie worden gezien. Naast de ICC bestaan criteriasets voor ME/CVS met afnemende specificiteit die een grotere populatie dekken, zoals de Canadian Consensus Criteria (‘Canadian’, 2003) en de Four-Symptom Criteria (niet in de tekst beschreven). In de figuur ontbreken de IOM-criteria voor ME/CVS (SEID), maar ook deze dekken een grotere populatie dan de ICC. De buitengrens van de populatie wordt gevormd door patiënten die alleen aan de criteria van de Centers for Disease Control and Prevention uit 1994 (‘Fukuda’) voldoen. Deze figuur geeft een vergelijking van de aantallen ME/CVS-patiënten weer en dus maakt geen inhoudelijke vergelijking tussen het soort patiënten dat onder de verschillende criteriasets valt.
Bron: Jason LA, Kot B, Sunnquist M, Brown A, Evans M, Jantke R, Williams Y, Furst J, Vernon SD; Chronic fatigue syndrome and myalgic encephalomyelitis: towards an empirical case definition. Health Psychology and Behavioral Medicine 2015; 3: 82-93."

English:

Spoiler: Explainer box in English (machine) translation

"Figure 1: Comparison of different criteria sets for ME/CFS by number of patients.
The 2011 International Concensus Criteria for ME (ME-ICC) are the most recent and stringent description of ME/CFS; patients who meet this set of criteria can currently be seen as the core of the ME/CFS population. In addition to the ICC, criteria sets for ME/CFS with decreasing specificity exist that cover a larger population, such as the Canadian Consensus Criteria ("Canadian," 2003) and the Four-Symptom Criteria (not described in the text). The figure lacks the IOM criteria for ME/CFS (SEID), but these also cover a larger population than the ICC. The outer limit of the population is formed by patients who only meet the criteria of the 1994 Centers for Disease Control and Prevention ("Fukuda"). This figure shows a comparison of the numbers of ME/CFS patients and thus does not make a substantive comparison between the types of patients covered by the different criteria sets.
Source: Jason LA, Kot B, Sunnquist M, Brown A, Evans M, Jantke R, Williams Y, Furst J, Vernon SD; Chronic fatigue syndrome and myalgic encephalomyelitis: towards an empirical case definition. Health Psychology and Behavioral Medicine 2015; 3: 82-93."

I'm only just noticing that the explainer box, while also saying that Fukuda defines the outer limit (of the intended population), acknowledges that this diagram does not "make a substantive comparison between the types of patients", but compares the numbers of patients falling under the different sets of criteria. So presumably, it really can't be used to justify viewing the different populations as nested subsets.

 

Before I begin, it's important to state that it's not just the criteria used that are the problem, but also the way in which participants in Lifelines were selected as having "CFS". (Besides other issues.)

Even if using Fukuda according to the Research Program would be fine (it isn't), there would still be the huge problem of the way in which those criteria were supposedly used - the Lifelines cohort would still be unsuitable for the Research Program ME/CFS.

Based on the information available, I see 6 Program requirements that weren't met by Lifelines. The criteria is just one of them.

 

Just to finish posting the relevant passages from the "Programmatekst" document, here is the continuation of the text posted and translated above. This comes under a new section header and is text explicitly defining how the criteria should be used within the research programme.

In Dutch:

Spoiler: Use of criteria sets in research programme (Programmatekst, p.9)

"2.2.3 Gebruik van criteriasets in het programma
Discussie over de sensitiviteit en specificiteit van verschillende criteria-sets voor ME/CVS maakt het dus moeilijk om voor een specifieke set te kiezen. Dat onderzoekers door de literatuur heen
verschillende definities van ME/CVS gebruiken maakt het moeilijk onderzoeksresultaten te vergelijken en zo kennis over ME/CVS op te bouwen. Hoe moeten onderzoekers binnen het biomedische
onderzoeksprogramma ME/CVS hun onderzoekspopulaties nu afbakenen?"

In ieder geval is van belang dat onderzoekers zich bewust zijn van de voor- en nadelen van het gebruik van verschillende criteria-sets. De Gezondheidsraad doet geen concrete aanbeveling voor
welke criteria-set gebruikt moet worden in onderzoek naar ontstaan en behandeling van ME/CVS. De stuurgroep van de onderzoeksagenda stelt dat in veel van dergelijk onderzoek de ICC nu een goed vertrekpunt zouden kunnen zijn. De Gezondheidsraad adviseert bij onderzoek naar een betere onderbouwing van de diagnose ME/CVS – en eventuele sub-diagnoses – alle kenmerken die
figureren als diagnostische criteria in de verschillende definities van ME/CVS mee te nemen. De stuurgroep van de onderzoeksagenda ME/CVS onderschreef dit advies. Van belang is dat onderzoeksvoorstellen hun definitie van ME/CVS steeds expliciet maken en laten zien hoe deze zich verhoudt tot al bestaande definities, patiëntengroepen en hypothesen over de pathofysiologie van
ME/CVS.

In English (machine translation, marginally checked and corrected):

Spoiler: Use of criteria sets in research programme (Programmatekst, p.9)

"2.2.3 Use of criteria sets in the program
Thus, discussion of the sensitivity and specificity of different criteria sets for ME/CFS makes it difficult to choose a specific set. That researchers throughout the literature use different definitions of ME/CFS makes it difficult to compare research results and thus build knowledge about ME/CFS. How should researchers within the biomedical ME/CFS research program delineate their research populations now?
In any case, it is important that researchers are aware of the advantages and disadvantages of using different criteria sets. The Health Council of the Netherlands does not make a concrete recommendation for which criteria set should be used in research into the development and treatment of ME/CFS. The steering committee of the research agenda states that in many such studies the ICC now form a good point of departure. The Health Council of the Netherlands advises that research into a better substantiation of the diagnosis of ME/CFS – and any sub-diagnoses – should look at all of the characteristics that figure as diagnostic criteria in the various definitions of ME/CFS. The steering committee of the ME/CFS research agenda endorsed this advice. It is important that research proposals always make their definition of ME/CFS explicit and show how it relates to pre-existing definitions, patient groups and hypotheses about the pathophysiology of ME/CFS."

"It is important that researchers are aware of the advantages and disadvantages of using different criteria sets."
I don't think the advice could be watered down any further...

This concludes all relevant passages from the "Programmatekst" document.
Next to this text, the Call for proposals is obviously also relevant.

 

This page of Lifelines Wiki provides more information on that:
https://wiki-lifelines.web.rug.nl/doku.php?id=cfs_diagnostic_score&s[]=fatigue

Note this statement:
"The CFS diagnostic score can be requested in the Lifelines catalogue or by mail (data@lifelines.nl)."

 

To add to that excellent list of questions by @Solstice , @FMMM1, if you were to write to Cindy de Boer again, you could also ask (so we have that on record once and for all in explicit terms):
"Will you determine CCC, ICC or IOM status in all Lifelines participants or only in the group already identified as having "Fatigue (CDC)" in accordance with the CFS Diagnostic Score used by Lifelines?"

 

So note, this is just about the use of CDC'94, not the surrounding issues with them (like Lifelines pretending to use current CDC criteria) or adjacent problems like the way they are applied.

Info from the research program, italics used to emphasise direct quotes:


The ZonMW Research Program ME/CFS requires that the research uses motivated criteria in line with the current state of the science.

The ZonMW ME/CFS Research Program clearly sets out what the intention is: high-quality biomedical research into ME/CFS according to current international standards. The Netherlands has a lot of catching up to do, and “all applications must link up with (international) scientific literature.”

Building a biobank and patient registry, which are “fed by the individual studies in the program”. is an important part of the program. Since there is no one standard criteria set for ME/CFS research, “an important consideration in the evaluation of projects in the program .. will therefore be which criteria set(s) the studies use, and why.”

The program names specificity as important. Plus, "Connection to the current state of science is also an important consideration in the choice for a definition of ME/CFS. Therefore, research applications within the biomedical research program ME/CFS seek good alignment with the (recent) scientific literature and the definitions of ME/CFS therein."

The program states: “In the literature, post-exertional malaise (PEM) has been described as a hallmark symptom of ME/CFS. PEM has therefore been made a requirement in more recent criteria sets for ME/CFS, such as the CCC, the ICC and the IOM. The CDC itself now also uses the IOM criteria from 2015 and no longer the CDC criteria from 1994 in which PEM was not a condition.”

The ICC criteria are called highly specific, while they do use a slightly different description of PEM. The IOM is named as less specific than ICC and CCC due to their development for practical, clinical use. [Research criteria are usually stricter than those for clinical use.]

The CDC criteria from 1994 are mentioned in the text as previously used criteria, but it is subsequently apparent from the text that they do not meet the requirements of the Research Programme: they are not specific enough, outdated, do not have a PEM as a requirement, do not match recent scientific quality standards. (See above) They are also not preferred by ME/CFS scientists and patients:

The ZonMw steering group of the project considered the ICC criteria a “good starting point”.

And “biomedical researchers in the questionnaire study seem to favor the use of the Canadian Consensus Criteria (CCC). Program day speakers, who talked about their research into the origins of ME/CFS, indicated that they use the International Consensus Criteria (ICC) in their ongoing research“

The questionnaire study referred to is a survey conducted by ZonMw among international researchers which can be found in the ZonMw Research Agenda: there were 22 votes for the use of CCC, IOM or ICC, and only 2 for Fukuda.

It is very clear from the text of the research program that grant applicants are expected to choose ICC or CCC, or possibly IOM: a criteria set, or variation thereof, that meets the modern requirements of international ME/CFS research and requires PEM.

Lifelines, and the ME/CFS Lines sub project, does not do this. They use the CDC '94 criteria, where the emphasis lies on "fatigue" (Lifelines also calls fatigue "the core symptom of CFS") and there is no requirement for PEM or neurological, immunological, or autonomic symptoms, unlike in the three current ME/CFS criteria sets.


Edited to tag @Medfeb

 

Quite!

 

The point with that quote is that elsewhere in the section on criteria the program mentions IOM's lesser specificity compared to ICC and CCC. If IOM might not be specific enough for the ME/CFS research program's aims, then CDC'94 certainly isn't.

 

That only works if you ignore...well...the whole core and goals of the research program really. It flies like a brick balloon.


Also, interestingly, under point 3.4, "population research", the Program actually sets requirements for the use of existing cohorts. It says:

"Research into the incidence and prevalence of ME/CFS within the Dutch population and research into environmental factors in the development of ME/CFS can be done in different ways, for example by using an existing population cohort. It is important here that ME/CFS is correctly defined and researched within the population cohort to be used. Due to shifting definitions of ME/CFS, such research is more appropriate in a later phase of the program. Research within an existing population cohort is expected to require additional questionnaires and tests selected by ME/CFS researchers."

 

I skimmed it and it was a bit odd, but I can't remember how. Only that at the time I found it peculiar that that image was used in the Program in such a way, but that it didn't matter in objecting to the grant approval.

 

What do you think the added value is of that? (I don't understand why it matters, and several sources are already clear it is on the LL-CFS cohort.)

I also personally think that by asking such a question you give the signal that what they plan to do (a paper inter-criteria analysis after all studies are done on Lifelines' dodgy CDC-94like "CFS"cohort) is debatable instead of a hard unacceptable.

 

Btw, update from the ME/CVS Vereniging (GT English), who sent a pro forma objection to ZonMw

And here's

Spoiler: the text of the pro-forma objection

June 3, 2023, Spijkenisse
Subject: Pro-forma objection decision grant ME/CFS research program grant
to consortium ‘ME/CFS Lines – A multidisciplinary consortium and biobank for unravelling
ME/CFS aetiology in Life Lines' and ensuing sub-projects.

Dear board,

By means of this letter we submit a provisional objection to the recently published
ZonMw decision (1) to form the consortium 'ME/CFS Lines – A multidisciplinary consortium and biobank
for unraveling ME/CFS aetiology in Life Lines', and the ensuing sub-projects, a
grant in the context of the first funding round of the research programme
ME/CFS. (2) More specifically, our preliminary objection is directed to the following project numbers:

i. 10091012110021
ii. 10091012110010
iii. 10091012110015
iv. 10091012110017
v. 10091012110019
vi. 10091012110023

For the time being, the grounds for our provisional objection are based on (presumed)
violations of the General Principles of Good Administration (abbb). This concerns
violations of the principle of due care (see art. 3:2 et seq. of the General Administrative Law Act
[Awb]), legal certainty and the principle of trust. This is a preliminary appeal,
because we are still awaiting the delivery and provision of substantive and relevant
documents that refer to (among others) the above project numbers. This follows from our Woo request dated April 8, 2023. We request that you send us the file as soon as possible.
so that we can supplement the grounds for the objection. After we file
have received, we request that you give us four weeks to do so.
In addition, we expressly wish to make use of the possibility of a hearing
(art. 7:2 Awb). We are willing to start the conversation with you as well as with the
consortium leader/lead party.

If you have any questions regarding this provisional objection, please contact us in writing to the above e-mail address.

etc.etc.





1)https://www.zonmw.nl/nl/nieuws/eerste-biomedisch-onderzoek-naar-mecvs-van-start; this concerns
not the actual decision, but a publication notice of the decision. Since the ME/CFS Association
has still not received a copy of the underlying decision, the objection period of 6
weeks still open given the publication date – the publication notice states no (other)
date of dispatch or objection period (see art. 6:8 paragraph 1 and 3:14 paragraph 1 Awb).
2) https://www.zonmw.nl/nl/onderzoek-results/disabled-and-chronically ill/programmes/programme-detail/research-program-mecvs/

in GT english

 

Thanks.
Apologies criteria/definitions aren't thing/my knowledge is limited --- I assumed that the "Lifelines" selection criteria were broader (3X) than the generally accepted ME criteria. Would it be possible to be in the Lifelines cohort but not to meet the criteria for some, or all, of these "CCC, ICC or IOM"? EDIT similarly would it be possible to be excluded from lifelines but meet "CCC, ICC or IOM"?
If so then "cleaning" the Lifelines cohort, i.e. to align with DcodeME criteria "CCC, ICC or IOM", seems a much larger job!

 

Yes this is exactly what I was thinking. The two Lifelines questions that are meant to capture PEM seem inadequate for the purpose of determining whether someone has PEM or not, therefore one cannot reliably determine whether the participant met CCC, ICC, IOM criteria.

https://wiki-lifelines.web.rug.nl/doku.php?id=fatigue_cdc

 

Perhaps you are right and asking that question does not add value.

That question isn't enough to elicit the information I'm interested in. So let me rephrase:

"The project description on the ZonMw website makes it clear that you will only evaluate those Lifelines participants who already fulfill Lifelines Fatigue (CDC) criteria for whether they also fulfill IOM criteria, CCC and/or ICC. But neither of the populations defined by the IOM criteria, the CCC and the ICC are necessarily subsets of the population defined by Fatigue (CDC).
Do you think IOM, CCC and ICC populations prescreened by Fatigue (CDC) will be representative of, respectively, IOM, CCC and ICC populations at large? Or, if not, will this just have to stand as one of the limitations of your study?"

I do find it important that it is clear and obvious that that latter point was pointed out to them right at the start.

For the rest, I don't think what "signal" I give them makes any difference. I do think they must by now have received the signal that Dutch ME/cfs patients as a whole find what they are planning totally unacceptable.

 

Hi,

The Lifelines cohort is a cohort of (from memory) about 160,000 people in the north of the Netherlands that Lifelines claim are representative of the Dutch population as a whole.
That whole study population received questionnaires, amongst which, since 2014, a questionnaire that (according to Lifelines) is adequate for determining (with the help of their "CFS diagnostic score" calculations) whether participants fulfill Fukuda criteria. The fact that their tools lead to at least 2900 people with Fukuda CFS in their cohort suggests they are overestimating prevalence of Fukuda CFS.

In the course of the ME/CFS Lines project now funded, they will study those participants now deemed fulfilling Fukuda criteria and determine (in some way yet to be made known) whether they (also) fulfill Canadian Consensus Criteria, International Consensus Criteria and/or Institute of Medicine Criteria.

It is possible to fulfill International Consensus Criteria without fulfilling Fukuda Criteria. (The ICC don't require fatigue.)
In any case, neither ICC, nor CCC or IOM criteria are simply Fukuda criteria plus extra requirements.
So determining ICC, CCC and IOM status only in people prescreened by (their version) of Fukuda, rather than in their whole cohort representative of the Dutch population, creates the problem that we don't know if those prescreened ICC, CCC and IOM groups are representative of ICC, CCC and IOM patients at large.

At least, that's my limited understanding of the situation.

 

If that's the case then the lifelines cohort can't easily be aligned with DecodeME selection criteria ---

 

Thanks guys/gals.