“Which medical research should be receive more funding” is a hugely important question, with hundreds of *billions* of dollars spent on medical research yearly. It’s also one that is not always approached in a rational and evidence-based way, which is understandable, as most people think about this question when they or their loved ones ends up suffering from a particular disease.
As an EA, it’s somewhat ironic that I started thinking about medical research because someone close to me became disabled from a horrible illness, but researching this illness gave me lots of ideas that could be more widely applicable to cause prioritisation within medical research. I’ll use this illness as a case study, using the ITN framework.
I’ve deliberately not named the illness yet, as there is significant controversy about its name. In fact, there are various controversies around this illness, which we’ll look at in more detail. The controversies both contribute to and are a symptom of its neglectedness, which makes it quite interesting for researchers and EAs to objectively investigate.
Here I’ll use the name myalgic encephalomyelitis, or ME. It’s an illness characterised by extreme fatigue, which in the most severe cases can lead to not being able to move the body at all, beyond basic functions like breating. It is commonly accompanied by pain. There is no cure, very few medicine to manage symptoms, and the cause is not understood at all. Researchers have observed immunological and neurological abnormalities, but that’s about it. Tens of millions of people worldwide fit the diagnosis, with about a quarter of them being homebound or even unable to leave their bed.
The history of controversy is a nasty one. It is now known that it’s a disease that affects the immune system, and diseases like that disproportionally affect women, for reasons still unknown. This is a well-established, empirical fact. But in the past, the condescending, patriarchal society would label this “mass hysteria”. The revised name became “Chronic Fatigue Syndrome”, which is a bit better, but still trivialises this crippling disease (“I’m always tired too”). This history continues in different forms, with some insurance companies and governmental bodies still labelling the disease as a “psycho-social disorder”. This is an obvious cop-out for a disease that has virtually no objective lab tests to confirm it, but which is very real nonetheless.
Diseases can be real — causing symptoms and suffering — and yet have no objective tests, simply because science has not advanced enough. This then causes a downward spiral: victims are shamed and blamed (“just get off your ass”), insurance companies see a way to improve their bottom line (“we don’t cover psychological conditions”), doctors are powerless at best and harmful at worst (“do some exercise, that’s good for everyone”), patients get desperate and turn to alternative medicine and conspiracy theories, people see that and decide that this disease really must be a sham, and finally researchers stay away in fear of their funding drying up or even losing their jobs.
This is very interesting to EAs. It’s like mis-pricing of stocks, where investors act emotionally instead of rationally. If we can identify diseases for which this happens, and “correct the valuation”, we could not only correct the amount of funding a cause receives, but potentially even break this downward spiral. We could attract funding from traditional sources which have eschewed these causes because of stigma. I don’t know of where to allocate funds to most effectively make that happen, be it in basic research, or public campaigns, or lobbying, or something else, but it seems a huge opportunity to me.
A standard measure of disease burden is DALY, Disability-Adjusted Life Years, where you count the number of premature deaths because of an illness, plus the number of “equivalent” years lost due to disability. What equivalent means here is tricky, and there are various ways of measuring it, based on quality of life, or loss of function, or how many years with a disability people are willing to trade in for one year of premature death, and so on. In the end a disease gets a “disability weight” (DW) to indicate how much suffering it causes, between 0 (perfect health) and 1 (death).
Because ME gets neglected by researchers, good data for determining the disease burden of ME is scarce. For example, ME was not included in the 2016 Global Burden of Disease (GBD) study. A recent study looked at two methods of estimating disability weights to come up with a weight of 0.46 (and for the one quarter of patients with severe ME, 0.76). It’s fascinating how this is estimated, and I highly recommend reading the underlying studies!
For comparison, here are the ME disability weights put in context (based on the 2016 GBD study). There are a ton of caveats in comparing these, but this should give you a rough idea.
|Condition||Disability weight (DW)|
|ME (weighted average)||0.46|
|Multiple sclerosis (moderate)||0.463|
|Multiple sclerosis (severe)||0.719|
|AIDS (without treatment)||0.582|
|HIV/AIDS (with treatment)||0.078|
|Anxiety disorder (severe)||0.523|
|Loss of one leg (without treatment)||0.173|
The other part is premature deaths. Suicide is at a ridiculously high rate for ME patients, about 17 times the national US average (compared with 2 times the average for cancer and MS patients and 6 times the average for patients with depression). There also seems to be a link with heart disease and cancer. Taking all that into account, plus the disability weights, plus a conservative estimate of about 1 million patients in the United States with ME, the estimated disease burden in the US is 714,000 DALY.
To get a sense of context here, compare this with 2015 US DALYs and NIH spending:
|DALY||NIH spending||spending per DALY|
|Multiple sclerosis: 0.28M||$94M||$331|
|Mental illness: 7.7M||$2263M||$292|
|Heart disease: 7.8M||$426M||$55|
Looking at the raw data, there is quite a bit of variation in funding, but estimated funding for ME per DALY is just insanely low. Using the previous analogy, this is almost literally mispricing in the market!
All of this is still too limited for well-weighted decision for EA standards. For example, how does this extrapolate to *global* disease burdens instead of just the US? How robust are the analyses and the underlying studies? What kind of error bars are we talking about when comparing numbers here? I couldn’t find answers to those questions, so this is fairly speculative, but the several-orders-of-magnitudes underfunding based on DALYs by the NIH does suggest that there might be something interesting here.
Now, underfunding doesn’t mean that it’s a good use of your dollars. Is there “room for more funding”?
I have two conflicting intuitions about this: first of all, since ME is so dramatically underfunded, any kind of research into the fundamental causes of the disease should find at least something, because there are such severe symptoms that basically no-one has looked into yet using modern methods. On the other hand, it could be hard to find someone competent because of the stigma and misunderstanding.
In the case of ME though, there seems to be some momentum. A few years ago, the director of the Stanford Genome Technology Center, Ron Davis, saw his son fell severely ill with ME, after which he started a research group to look into the disease. He also started a foundation and got endorsements for ME research from his extensive network, including several Nobel prize winners and NAS members. When you start looking, you find similar stories, such as the Cornell ME/CFS center, which was founded by someone whose family member has ME.
These people are highly skilled, and might never have gotten into ME research if it weren’t for family members getting it. But now they are highly motivated, and in the position to break out of the downward spiral of stigma. If they can even find a *hint* of a physical cause (“biomarker”), the names of institutions like Stanford or Cornell would be behind a legitimisation of the disease. This could lead to more funding, more decent research, and even better outcomes for patients in the short term, through increased awareness and education among doctors.
Timing is crucial here. You want to have a good team with a research proposal that has some chance of finding something, so you want to wait for that. But you also don’t want to wait too long, or the effort might lose momentum — researchers might give up or retire, a group of well-intentioned Nobel Prize winners may fall apart, and so on.
In the Stanford case, it might be the perfect time for an intervention by EAs. They have a plan of doing a wide range of state-of-the-art tests on a small number of very severe patients, like the son of the director. This both saves money and increases the likelihood of finding something, as any biological effects will probably be more pronounced in such sick patients. They can do these tests cheaply because their lab has (co-)invented some of the technology that they’re testing with. They raised enough funding from grants and private funds to collect the samples and get preliminary results, but need more money to continue doing tests and analysis. Money is actually the blocker, so each additional dollar would immediately be put to use.
For an underfunded, misunderstood, and important disease like ME, and others like it, it’s hard to say where exactly to spend your money to make a difference. There are a number of different things to target, and they all reinforce each other: more funding for research, more public awareness, better education of doctors, and so on. For ME, a lot of groups focus on public awareness, with online campaigns, protests, and a recent award-winning documentary by a Harvard student with ME. It looks like those efforts are helping, with recent results including revised government guidelines and a surprisingly huge anonymous cryptocurrency donation. That said, I suspect that additional dollars would be best spent on medical research.
When learning about ME, I had a lot of ideas relevant for EA. Some might be already known, or perhaps even debunked, but maybe there are some new ones in here, too:
- Stigma could be an indicator of neglected diseases.
- Association with alternative medicine and questionable practices could be such an indicator too. There could be more to it when you dig deeper, as people can get desperate for a solution.
- Stigma and association with questionable practices can amplify the neglectedness of a disease.
- Basic research could have an outsized impact on such diseases, by breaking through stigma.
- When removing stigma from a field of research, that could attract funding and scientists, thus amplifying our dollars.
- This effect might be bigger than that of activist campaigns, per dollar contributed.
- In the long term there could be a lot of room for funding in diseases with low funding per DALY.
- In the short term however, it might be hard to find good research worth contributing to.
- It might be worth finding top researchers who have a family member suffering from a disease, as they will be motivated.
- This will be easier the more widespread a disease is, thus correlating with its importance.
- I think proper timing in selecting good research is key, in order to accelerate something that has some momentum.
I’m still an EA noob, but I suspect that a small amount of funding towards top research into diseases like this could be quite competitive, especially compared to other interventions in the developed world. What do you think?
Thank you for this thoughtful and thorough post! I've been following this complex chronic condition for many years, as I have a personal connection to it. Fortunately, there has been significant progress made in leveraging awareness, funding, and research, particularly over the past year based on the connection to COVID and a post-infectious disease process. Thought I'd share links to a couple of organizations leading these efforts. One just had a fundraising campaign in May, along with research updates. The other is promoting a campaign that doubles donations 1:1, up to $1M, through the end of this month so only 1 day left!
Open Medicine Foundation
Here's another related organization (studying the complex and dynamic relationship between microorganisms and human physiology/pathology) that I recently came across:
PolyBio Research Foundation
Your article doesn’t mention Systemic Exertion Intolerance Disease (SEID). It’s the new name the Institute of Medicine (IOM) gave the disease. Given that we are on the internet it’s helpful to work all relevant keywords into an article like this even if you don’t like the new name.
It does seem like there are important areas where medical research is inadequate. I'll suggest that part of the problem is inadequate effort devoted to treatments that aren't protected by patents.
It looks like some unknown fraction of ME/CFS is caused by low thyroid hormone levels. "Subclinical" hypothyroidism has symptoms that are pretty similar to those of ME/CFS. They are usually distinguished by TSH tests. [TSH is the standard measure of thyroid levels; there are a number of other options, none of which are ideal].
Here's speculation that we should distrust TSH results. (There's a more detailed and very verbose version of that speculation here).
There's plenty of confusion about when it's wise to increase a patient's thyroid hormone. E.g. this small RCT study which gave a standard T4 dose, rather than adjusting the dose to achieve some measure of optimal hormone levels. The reported TSH levels of 0.66 in patients receiving T4 suggest that many patients got more than the optimal dose, and/or didn't convert T4 to T3 well.
In contract, two smaller uncontrolled studies (here00014-0/abstract) and here) reported good results from T3 treatment for treatment-resistant depression (H/T Sarah Constantin). Plus there are lots of anecdotal reports of benefits (see mine here).
There are real dangers from overdoses, and it's unclear how well researchers have measured the benefits, so it's easy to imagine that most doctors are erring on the side of inaction.
My intuition says that there's plenty of room for making protocols that more safely determine the optimal dose. I don't have enough expertise to estimate how tractable that is.
Another area where EAs might possibly provide an important benefit is Alzheimer's. There have been some recent claims that there are strategies which substantially prevent Alzheimer's or reverse it in early stages. As far as I can tell, these claims aren't prompting as much research as they deserve.
Some parts of those strategies are backed by small RCTs published in 2013 and 2012, and yet the first Google search result for Alzheimer's is still a page that says Alzheimer's "cannot be prevented, cured or even slowed".
I expect good research about Alzheimer's to be too expensive for EAs to fund directly, but it seem like we should be able to do something to nudge existing research funding into better directions.
ME/CFS (the currently accepted name in the US) is a physiological disease. This is beyond dispute, and no longer a debate in the medical and scientific community. At least in the United States.
US CDC: "Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, long-term illness that affects many body systems."
US National Academy of Medicine: ME/CFS "is a medical — not a psychiatric or psychological — illness."
New York State Department of Health: ME/CFS is "a multi-system disease associated with neurological, immunological, and energy metabolism impairment."
Yes, but only very recently so. For example, it's only a few months ago that the CDC removed language and recommendations that were remnants of the belief that it is psychological. See the article that I linked at the end of the post for some background there (https://www.npr.org/sections/health-shots/2017/10/02/554369327/for-people-with-chronic-fatigue-syndrome-more-exercise-isnt-better). And it's likely that there are plenty of doctors who haven't followed these developments closely and would still believe it's not a physiological disease.
This was intended to be a reply to casebash, who was questioning whether ME/CFS was psychological. It was not meant as a comment on the article itself. My apologies for the confusion.
Thanks for this writeup. I found it thoughtful and compelling.
My understanding is that ME is real, serious, and understudied/underfunded. Perhaps the core reason it's understudied is that it's unclear where to start, physiologically speaking -- there's a lot of ontological uncertainty in terms of what this thing is that sometimes cripples people.
This is sometimes solvable by throwing resources at the problem, and sometimes not.
It might be helpful to survey some other diseases that followed a similar trajectory (mysterious crippling conditions that later resolved into known diseases with known causes and known treatments) and see if there are any general lessons to learn. My expectation here is that often, what makes a mystery disease 'make sense' is a new method that gives a novel/fresh window into physiology. Celiac disease could be an interesting case study: it was hugely mysterious (and hugely underdiagnosed) until (1) we got a decent IgG screen, and (2) we started to understand how gut permeability works.
I'd also suggest that you may be a little too cynical about alternative medicine; there's a huge amount of snake-oil there, but alternative medicine is also highly heterogeneous, exploring a lot of the possibility space. There will be a lot of bs, but there often are some pearls as well. Mainstream medicine is also not particularly known for immediately finding these pearls and synthesizing them back into the medical literature, so I think it's also plausible that a viable way to make progress on this problem is to survey what alt-med thinks it knows about ME, filter the bs out, and see if there's anything left that can help mainstream medicine understand what ME is and what general class of treatments might help.
After different forms of resting https://curetogether.com/chronic-fatigue-syndrome/ig/treatment-effectiveness-vs-popularity Low-Dose Naltrexone seems to be the treatment that was reported as most beneficial on CureTogether for CFS. Fortunately there’s an ongoing clinical trial to test this treatment.
I think the fact that there are some pearls in alternative medicine but there no efficient way to find them is a more fundamental problem that is it’s own cause worth looking at. Our at LessWrong I wrote proposed Prediction-based Medicine. It would be possible to create a startup that puts Prediction-based Medicine to work and afterwards it would be possible for patients to go to alternative medicine providers who can reliably predict the treatment success they have for the patients.
The startup would need a good team and some funding but Musk-level funding wouldn’t be required to put the idea effectively to work.
The first link seems to be dead by now, the second one moved. Here are the most recent (archived) versions that I could find:
If I understand it correctly, then the study you mention is scheduled to end in August 2022, this year: https://clinicaltrials.gov/ct2/show/NCT02965768 (backup)
It contains only 30 participants, but still better than nothing.
All great points, thanks!
There seems to be some confusion about scale--from importance--in regard to neglectedness (ITN). One should also consider how pervasive the medical condition is in the world. How common is it? Is it a very rare medical condition? Does it affect a certain cohort? Just something to keep in mind.
Reg-charity.org "Prioritising causes"
EA Forum article1
EA Forum article2
80,000 Hours "Accessing Importance"
PS ~ When describing EA to others, a big question is, "What is 'effective' charity?" A common misunderstanding is mistaking 'effective' charities to be preordained or forced. As any EA knows, evaluation is key. Better understanding will come when using complementary diction, such as "scale" and "solvability" (see at least the first link above).
Yeah, the DALY metric I used in this article takes into account how common it is.
As long as we're talking about medical research from an EA perspective, I think we should consider funding therapies for reversing aging itself. In terms of scale, aging undoubtedly is by far the largest (100,000 people die from age-related diseases every single day, not to mention the psychological toll that aging causes). Aging is also quite neglected - very few researchers focus on trying to reverse it. Tractability is of course a concern here, but I think this point is a bit nuanced. Achieving a full and total cure for aging would clearly be quite hard. But what about a partial cure? What about a therapy that made 70 year olds feel and act like they were 50, and with an additional 20 years of life expectancy? Such a treatment may be much more tractable. At least a large part of aging seems to be due to several common mechanisms (such as DNA damage, accumulation of senescent cells, etc), and reversing some of these mechanisms (such as by restoring DNA, clearing the body of senescent cells, etc) might allow for such a treatment. Even the journal Nature (one of the 2 most prestigious science journals in the world) had a recent piece saying as much: https://www.nature.com/articles/d41586-018-01668-0
If anyone is interesting in funding research toward curing aging, the SENS Foundation (http://www.sens.org) is arguably your best bet.
unsure why this was downvoted. I assume because many EAs think X-risk is a better bet than aging research. That would be a reason to disagree with a comment, but not to downvote, which is snarky. I upvoted for balance.
I'm not sure I'd put it only on X-risk people. My understanding is that disease burden and DALYs are calculated using as a reference the highest life expectancy of any country by gender, which was previously Japanese women (now South Korean women?), and somewhere between 80 and 90 years. This means that deaths after this reference life expectancy simply don't count towards disease burden at all. I'd like to hypothesize that this and some of the downvotes may be due to what I suspect is a common intuition (perhaps not common in EA; I don't know): everyone ought to have an overall good life with a decent lifespan, i.e. "fair innings".
This "fair innings" might be part of why EAs are generally more concerned with global health and poverty than anti-aging. Maybe the stronger evidence for specific poverty/health interventions explains this better, though.
Mostly guesses on my part, of course.
One of the biggest challenges is trying to even figure out how likely it is caused by something physical vs. a psychological root cause. It is a very controversial topic, to say the least. I spent about an hour looking into this, but I wasn't really able to get anywhere, at least without any knowledge of the field or where to find reliable information.
That's fair, a lot of this are recent findings. Which is why I think it's interesting to EA, since there isn't much mainstream understanding and funding yet.
I would say if you're going to spend an hour researching, I'd look at the 2015 Institute of Medicine report, which contains most of the current state of the art (http://www.nationalacademies.org/hmd/Reports/2015/ME-CFS.aspx). Which is very little. But they do cite quite a few studies on physical manifestations of the disease, in an attempt to establish diagnostic criteria (e.g. physical differences during exercise stress tests).
There obviously are some more findings since then, but since funding is so low there isn't that much progress since 2015. ;)
Also, what's great about EA is that we're not just individuals with an hour here and there to spare. We have entire organisations dedicated to researching causes and interventions. They could take a couple of controversial diseases like this (I only had time to look into this one) and properly research what's going on, and how much funding in the right places would help.
They might find that none of this is useful to spend money on. Or they might find some gems. I think it's worth finding out!
It's not either/or. It's likely not to be a single disease - would probably be more accurate to call it a syndrome.
Mind-Body dualism isn’t a productive framework. For many diseases you have a mix of “physical” and “psychological” effects.
I think the general scientific consensus is that it's a physiological condition. But I don't think it matters whether it's psychological or not, anyway - it's just as disabling and underfunded either way.