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

You could respond to her that her credentials weren't in question but that you'd like to know if the cohort she's going to be using is selected using the criteria set out by the research program. That is the CCC, ICC or IOM criteria for ME. And if people are clinically diagnosed. If they aren't, are they planning to diagnose them according to CCC, ICC or IOM criteria to find out if they are in fact ME-patients?

 

Also how PEM will be assessed. The idea is to find out if PEM will be assessed with some vague question like "Do you get more fatigued after activities?" or something more specific.

We really need a good PEM questionnaire. The DePaul questionnaire is not good in my opinion and there isn't anything else.

 

That's a pretty fundamental gap that you've flagged, and it also explains a lot. Including the unhelpful confusion of what PEM is - because the work hasn't been done on finding out what we all mean by it. Indeed it probably varies not only by severity but also what you've done/has caused it, so how on earth without a lot of research with experience pwme you'd be able to put together something those who are new/not yet diagnosed could recognise in themselves I don't know.

And because of that difference in severities and vulnerabilities and 'load' in general lifestyle it isn't easy to do a 'test' where you can expect a certain amount of PEM looking like x at a certain time period necessarily - or can you?

Which is why the 2-day CPET was such a helpful breakthrough. It feels something psychometric might be possible too (and would at least show fatigability if not PEM, but would be interesting to do the 2-day format, post physical activity and post cognitive activity at different timeframes - or just something that could be used daily for a fortnight alongside a diary of activity to show time-lags) that could show tiredness patterns in function that people mightn't notice because 'fatigue' is different when you think about having a cup of coffee and feeling better vs whether your function is as if you weren't tired in the first place.

 

PEM is so complex that it requires more than one question and some explanation.

One aspect of PEM that might be least susceptible to misinterpretation is impaired next-day functioning. Feeling worse after activity is too vague and could be interpreted to include ordinary phenomena like delayed onset muscle soreness or even just feeling particularly fatigued shortly after stopping exercise.

 

Just wanted to add that you can get straight to the point with her, it's common practice in the Netherlands to be direct. So if you want to reply I would craft it so that there's only the questions you want to see answered. No room for ambiguity:

Hi Cindy,

Your credentials aren't in question. What I would like to know however if the cohort that you will be using is in accordance with the initial ZonMw-program. That is using the CCC, ICC or IOM-criteria. Are these people clinically diagnosed using those criteria? If they aren't, are you planning to get them diagnosed by a clinician using the CCC, ICC or IOM-criteria to make sure they have ME?

I am also curious what definition of PEM you have used to select these patients.

With high regards,

Name of sender

 

Something like that.

 

The kisses at the end are a bit much, but apart from that, it's a good reply draft.

 

Fill in your name on the x's was what it was meant to represent, hahaha.

Edited to clarify.

 

I know (maybe I should have added an emoji, but it was very Morning); it just gave me a good chuckle this morning, as my brain read it like that.

 

The CDC symptom questionnaire (attached) has a set of questions about fatigue and then the frequency, severity, and duration of 18 different symptoms plus depression. A CFS case requires the presence of fatigue plus any 4 of the 8 Fukuda symptoms. The other 10 questions and the depression question are not used to identify a case. (IOM requires symptoms be moderately severe and presence at least have the time)

18 of the Lifeline questions map to these 8 Fukuda symptoms (memory and concentration count as one of the 8). The other 2 questions are about depressive feelings which they say is supposed to help increase the diagnostic value.

The biggest differences in the symptom questions that both ask are:

1. Wording of PEM - Lifeline's is "Worsening of complaints after physical activity" and CDC's is "unusual fatigue after exertion"
2. Different question format - CDC asks about severity, frequency, and duration of symptoms whereas Lifeline asks about frequency and duration.
3. CDC asks about symptoms over last month while Lifelines asks about them over the last 6 months.
4. I didn't see a set of rules or algorithm on how Lifeline would use the answers to these questions to define a case. For instance, do they just require the presence of 4 of 8 symptoms for 6 months or do they also consider frequency?

They are referencing a CDC paper as validation for the instrument but I'd think the differences are enough to call that into question.

Edited to add: The CDC symptom inventory is no longer in use - largely because of deficiencies in the nature of the questions. For instance, they do not ask about OI, a key symptom. And their PEM question is bad.

 

(bold added)

@Solstice - Do you know if the requirement to use the CCC, ICC, or IOM is listed anywhere on the ZonMW research program site or in their call for proposals? I looked on the site but didn't see it.
That's a helpful statement for efforts elsewhere to get rid of Fukuda.
Thanks in advance

 

I've read it but I don't recall where. I'm sure someone here knows.

 

Thank you for providing that document and for shedding some light on how it differs from the Lifelines tool!

 

I do think Fukuda was not ruled out in a straightforward manner, but statements in the ZonMw documents can certainly be interpreted as implying that Fukuda criteria should not be used. They read like highly negotiated compromise passages to me (meant to be acceptable to patient representatives, but also to Dutch CFS researchers who have only ever used Fukuda criteria), but that's just my personal impression.

For context:
After the Dutch Health Council published their advice on ME/CFS in 2018, research funding organisation ZonMw was tasked with developing a national research agenda for ME/CFS. It was presented to the Minister for Medical Care and Sports (sic!) in December 2020.

Based on that research agenda, a research programme was then developed and published in October 2021.
(Download link to the 'programmatekst' (programme text), in Dutch, here: https://www.zonmw.nl/sites/zonmw/fi...onderzoeksprogramma-MECVS_zonder-bijlagen.pdf)

In December 2021, the call for proposals was published.
(Download link to the call, in Dutch, here: https://www.zonmw.nl/sites/zonmw/fi...dieoproep_consortia_cohortonderzoek_mecvs.pdf)

Both the "programme text" and the call for proposals contain statements about the criteria to be used. I think @Arvo has already quoted them at some point in this thread. I'll have a look and try to find the relevant quotes now.

 

To start with, here are relevant quotes from the "programme text":

On page 7 and 8 under "2.2.2 Criteriasets voor ME/CVS" ("2.2.2 Sets of criteria for ME/CFS"):

In Dutch:

Spoiler: Dutch text on criteria in "Programmatekst" document

"2.2.2 Criteriasets voor ME/CVS
Voor de individuele onderzoeken bínnen het programma kan het maken van een strakke afbakening van de onderzoekspopulatie juist heel belangrijk zijn. Het vergelijken van onderzoeksgroepen is alleen mogelijk met een goede beschrijving van die groepen. Op basis van symptoombeschrijvingen zijn de afgelopen jaren diverse sets van criteria opgesteld voor ME/CVS die onderzoekers daarbij zouden kunnen gebruiken. Die criteria-sets dekken (gedeeltelijk) overlappende groepen patiënten, waarbij de ene set tot een beperktere ME/CVS-populatie komt dan de andere (zie figuur 1). Veelgebruikte criteriasets zijn:
− De criteria voor CVS van de Amerikaanse Centers for Disease Control and Prevention (CDC) uit 1994,
− De Canadese Consensus Criteria (CCC) voor ME/CVS uit 2003,
− De Internationale Consensuscriteria (ICC) voor ME uit 2011,
− De criteria voor ME/CVS (SEID) van het Amerikaanse Institute of Medicine (IOM) uit 2015.

In de keuze voor het gebruik van de verschillende criteria-sets speelt met name de specificiteit een belangrijke rol. Zo adviseerde de Gezondheidsraad om de Oxford-criteria niet meer te gebruiken, omdat die een te brede en te heterogene groep definiëren. In de literatuur wordt ‘post-exertional malaise’ (PEM) als kenmerkend symptoom van ME/CVS beschreven. PEM is in meer recente criteria-sets voor ME/CVS, zoals de CCC, de ICC en de IOM, dan ook als voorwaarde gesteld. De CDC zelf gebruiken inmiddels ook de IOM-criteria uit 2015 en niet meer de CDC-criteria uit 1994 waarin PEM geen voorwaarde was. De IOM-criteria zijn echter ontwikkeld als praktisch instrument in de kliniek en dekken een wat bredere groep patiënten. De ICC bouwen voort op de CCC en komen tot de meest smalle definitie van de ME/CVS-populatie. Hoewel de ICC in hoge mate specifiek zijn, gebruiken zij een eigen, iets andere definitie van PEM, die net weer een iets andere groep patiënten lijkt te vangen dan andere definities.

Aansluiting bij de actuele stand van de wetenschap is ook een belangrijke overweging in de keuze voor een definitie van ME/CVS. Daarom moeten onderzoeksaanvragen binnen het biomedische onderzoeksprogramma ME/CVS goed aansluiting zoeken bij de (recente) wetenschappelijke literatuur en de definities van ME/CVS daarin.

De activiteiten die hebben plaatsgevonden binnen het traject van het tot stand komen van de onderzoeksagenda ME/CVS geven inzicht in het gebruik van criteria-sets voor ME/CVS in lopend onderzoek. Biomedische onderzoekers in het uitgezette vragenlijstonderzoek leken een voorkeur te hebben voor het gebruik van de Canadese Consensus Criteria (CCC). Sprekers op de programmadag, die vertelden over hun onderzoek naar het ontstaan van ME/CVS, gaven aan in hun lopende onderzoek de Internationale Consensus Criteria (ICC) te gebruiken. Uit de werksessies bleek dat bijvoorbeeld de UK ME/CFS Biobank (UKMEB) gebruik maakt van zowel de CDC-1994-criteria, de CCC, als de IOM-criteria."

Give me a second to make and check a translation...

 

I have relevant quotes ready in a doc. If still necessary, I'll drop them here after lunch, that saves you effort @MatthiasRiem

The reseach program and research agenda indeed do not contain the precise sentence "projects must use ICC, CCC or IOM", but it is clear from the text that that -or a variant of it- is expected. It is also imossible to interpret both documents as saying using CDC '94 is ok, even more so in the way Lifelines uses them.

Edited to add: Lifelines are aware of this, see how much effort they make in being hazy about using Fukuda instead of the current CDC criteria (IOM)

 

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

Spoiler: English translation of passage on criteria in "Programmatekst" document

"2.2.2 Criteria sets for ME/CFS
For the individual studies within the programme, creating a tight demarcation of the research population can be very important. Comparing study populations is only possibly with a good description of those populations. Based on symptom descriptions, in recent years, various sets of criteria have been formulated for ME/CFS that researchers can use. These criteria sets cover (partially) overlapping groups of patients, where the one set comes to a more limited ME/CFS population than the other (see Figure 1). Common Criteria sets are:
− The criteria for CFS from the U.S. Centers for Disease Control and Prevention (CDC) 1994,
− The 2003 Canadian Consensus Criteria (CCC) for ME/CFS,
− The International Consensus Criteria (ICC) for ME from 2011,
− The American Institute of Medicine (IOM) criteria for ME/CFS (SEID) from 2015.

In the choice for the use of the different criteria sets, in particular, the specificity plays an important role. For example, the Health Council recommended that the Oxford criteria should no longer be used, because they define too broad and too heterogeneous a group. In the literature, 'post-exertional malaise' (PEM) is described as a characteristic symptom of ME/CFS. Thus, PEM is 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. However, the IOM criteria have been developed as a practical tool in the clinic and cover a somewhat wider group of patients. The ICC build on the CCC and come to the narrowest definition of the ME/CFS population. Although the ICC are highly specific, they use their own, slightly different definition of PEM, which seems to capture a slightly different group of patients than other definitions.

Alignment with 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 ME/CFS research programme must connect well with the (recent) scientific literature and the definitions of ME/CFS therein.

The activities that have taken place within the process of establishing the ME/CFS research agenda provide insight into the use of criteria sets for ME/CFS in ongoing research. Biomedical researchers in the questionnaire study [M.R.: which ZonMw conducted] seemed to have a preference for the use of the Canadian Consensus Criteria (CCC). Speakers at the program day, who talked about their research into the etiology of ME/CFS, indicated they use the International Consensus Criteria (ICC) in their current research. The work sessions showed that, for example, the UK ME/CFS Biobank (UKMEB) uses both the CDC-1994 criteria, the CCC, as well as the IOM criteria."

 

Thank you, @Arvo, I'll take you up on that offer since doing this fries my brain more than I expected.
I will make an attempt, though, to post and translate the continuation of the passage I just posted.

I agree with you. Still using Fukuda in the context of this research programme puts some strain on your logical faculties...

 

Thanks for the information and for the documents, @MatthiasRiem and @Arvo. Very helpful and answers my question

I agree it strains logic to use Fukuda but I see some here also who still use it. But I found this statement on page 8 of the research program document - might be enough to give wiggle room to those so inclined

The outer limit of the population is formed by patients who meet only the 1994 Centers for Disease Control and Prevention ("Fukuda") criteria. ​

 

That passage is followed by a diagram which is either from or based on (haven't read that study, so can't tell):
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.
(Thread here: https://www.s4me.info/threads/evalu...case-definition-2022-conroy-jason-et-al.24829)


That diagram (attached to this post) is highly problematic, since it presents the populations identified by the differents sets of criteria as nested subsets: the ME-ICC population as a subset of the ME/CFS population identified by the CCC and the latter as a subset of the population identified by the Fukuda criteria.
The text of the "Programmatekst" document seems to vaguely acknowledge that this is not quite true when it says about the ICC: "Although the ICC are highly specific, they use their own, slightly different definition of PEM, which seems to capture a slightly different group of patients than other definitions."
That sentence just wouldn't make sense on the assumption that the populations identified by any of the other criteria contain all of the patients identified by the ICC.

They still chose to include that diagram and I think this might turn out to be a crucial justification for what Lifelines / ME/CFS Lines is about to do: The only viable interpretation for what has been stated publicly about ME/CFS Lines seems to be that they are going to identify ICC and CCC groups within the population of participants that they claim satisfy the Fukuda criteria in Lifelines.
I fear that the problematic fact that those participants were pre-selected by (Lifelines' version of) Fukuda will not be given sufficient consideration.