I’ve only skimmed this but let me give a bunch of info that seems relevant. (As I understand it, the question is whether low thyroid levels could cause chronic fatigue and fibromyalgia). For background, I am a junior doctor with no specific experience in endocrinology and support healthy scepticism towards the medical establishment:
Thyroid hormones are of course the first thing that one thinks of in people with low mood. Sometimes one will check the T4 and T3 as well as the TSH.
it is also one of the first things that one would research and it looks like there are plenty of papers checking hormone levels in these conditions.
People with hypothyroidism usually have high TSH. It would be surprising if this was different for people with fibromyalgia unless they had a specific insensitivity to thyroid hormone, which seems like a different hypothesis.
people with hypothyroidism usually don’t complain of pains in the same way as people with fibromyalgia.
people with fibromyalgia usually have a high sensitivity to slight painful stimuli in a way that I’ve never seen from people with hypothyroidism.
I also must admit that the since the post seems to me to be not just wrong but also very slow-moving, I haven’t read all of it. I would suggest rewriting this in a few paragraphs with citations to get feedback on a more brief version.
A likelier solution would be that pain-sensitivity and vulnerability to demotivation and fatigue are just (mostly additive) polygenic traits. Look to partially confirm this in 0-5 years when the first GWAS come out and demonstrate that thousands of genes make these diseases more likely, similarly to IQ and height.
Hi Ryan, thanks. My point is that ‘hypothyroidism’ is defined by high TSH. I wonder if it’s possible to have ‘hypometabolism’ or ‘all the symptoms of hypothyroidism’ whilst having a normal or even low TSH and maybe normal levels of the blood hormones too.
to answer your points:
(a) Yes, agreed. Only wrinkle here is that labs often refuse to check T4 if TSH is normal. This has happened to me twice despite my doctor specifically requesting an FT4 test. And I personally know someone who had CFS for years and lots of expensive NHS and BUPA and privately paid treatment without any thyroid test except for TSH.
(b) Yes, but if you’ve already removed all the people with strange hormone levels (because they’re hypothyroid, and so they don’t have CFS or FMS), then of course you’ll find normal levels in the remaining cases.
(c) Agreed, because hypothyroidism is defined by TSH. My hypothesis is exactly that many cases of FMS/CFS are ‘something wrong with the thyroid system that doesn’t show up on laboratory hormone level tests’.
(d) Hypothyroidism has lots of famously non-specific symptoms. Do hypothyroid patients sometimes complain of pains in the same way?
(e) that’s interesting and surprises me. I was under the impression that exactly that kind of widespread pain was one of the (many possible) symptoms of hypothyroidism. I’ll go and look.
Thanks ever so! I’ve added the explicit hypothesis to the summary. I’ll go and see what I can find out about pain in hypothyroidism/fibromyalgia.
a) This is a bit misleading. I’ve never had a lab refuse to do any test as simple as T4. It’s more a matter of how you communicate it. If you as for “thyroid function tests” or “TSH, T3, T4″ without clearly explaining, then they will usually stop at a normal TSH.
b) Most people diagnosed with CFS have had their thyroid levels checked but is this necessarily so for fibromyalgia? I don’t think so. Also there are studies where they stimulate release of thyroid humans. There are literally hundreds of highly relevant studies here.
c) Aren’t there things like thyroid receptor abnormalities that have different biochemistry but similar presentation to hypothyroidism? (And wildly different to fibromyalgia?) One has to look into this.
d) usually it’s just tiredness and slowness isn’t it? The fact that hypothyroidism presents so generally actually makes it less likely, not more likely to bear a specific connection here.
e) people with fibromyalgia often recoil if you try to examine them, take blood etc in a trait that they largely share with people who are anxious or have mental health issues with psychosomatic complaints.
What is needed here are similarities that are specific to these conditions and that are shared, whereas here it is the aspects that are the most general that are shared but the main facets of each condition are quite different and overall the two conditions don’t blur together in an interesting way.
At the fourth attempt, my doctor managed to get the local lab to test TSH,T3 and T4 simultaneously. He had to ring them up and ask them in person, apparently. It turns out that I’ve currently got TSH~2.5, and FT4,FT3 low-in-range. Given that that looks like central hypothyroidism, and that’s under the influence of 1 grain/day of desiccated thyroid, we’ve decided we that we have no clue, and I’m carrying on messing around with random thyroid drugs aiming for relief of symptoms (which are all gone, but I keep having to up the dose to keep it so).
Basically Christ knows. If I’m not medically unique, there’s something very funny going on.
That’s what I was expecting, but 2.5 isn’t suppressed, it’s actually quite high compared to the average for healthy people, (or at least normal, depending on what you think normal is). And roughly the same as it was at the start of all this. And both the free hormones look low. You’d think adding a fair bit of thyroid to a healthy system would have bumped up the free hormones and maybe lowered TSH to somewhere like the hyperthyroid range.
What’s really weird is that I’ve tripled the dose of NDT since the last time I had blood drawn, and my TSH has gone up slightly in response. I thought I’d be seriously suppressing my own system by now.
It’s possible that I’ve just developed a primary gland failure, but that’s weird because there was no sign of it when I first showed severe symptoms.
Ok so your TSH is normal and your T3/T4 are low in the normal range because you’ve replaced them with some T1/T2. Every value is in the normal range. Problem?
It makes no sense at all to call it pituitary failure (central hypothyroidism) - that would imply low TSH. You could argue that it’s successfully medicated peripheral hypothyroidism if anything, though that’s a stretch.
Ryan, this is great, I came here for an argument! Thanks. (“I wish to believe ‘snow is blue’ if and only if snow is blue”)
(a) OK, can we agree on “In most cases with ‘normal’ 0.3<TSH<5.5, TSH is the sole test performed”?
(b1) I don’t know, but given that FMS includes ‘brain fog’ and ‘tiredness’ I’d be surprised if many people with it haven’t had a TSH test. I would be surprised by the existence of people who only have the tender points and no other hypometabolic symptoms. Do we know what proportion that is?
(b2) “Also there are studies where they stimulate release of thyroid humans. There are literally hundreds of highly relevant studies here.” I don’t quite understand what you’re saying here. Can you link to a couple? Google scholar “fibromyalgia and thyroid” gives top hit: http://europepmc.org/abstract/med/1512769, Neeck G , Riedel W “Thyroid function in patients with fibromyalgia syndrome.”, in which they find abnormalities in a thyroid hormone releasing test in fibromyalgia patients. Doesn’t that support me?
(c) There are forms of hypothyroidism that don’t show up on the TSH test certainly, ‘central hypothyroidism’ and ‘peripheral resistance to thyroid hormone’, which have the same presentation but normal TSH. ‘Central’ should give you normal TSH but low T4 and T3. ‘Peripheral’ should be normal in all respects. But they’re thought to be vanishingly rare, and as far as I know, CFS/FMS people aren’t tested for them. In fact presumably the only way to test for them would be a trial of thyroid hormones! That’s kind of my point.
(d) Not just tiredness and slowness. It’s more of a general metabolic collapse. And which systems fail first seems to be random, which is why it’s so difficult to diagnose clinically.
(e) I’d expect anyone with widespread pain to recoil if you tried to touch them.
“What is needed here are similarities that are specific to these conditions and that are shared, whereas here it is the aspects that are the most general that are shared but the main facets of each condition are quite different and overall the two conditions don’t blur together in an interesting way.”
John Lowe appears to have known the rheumatology and endocrinology literature backwards, and claimed that every symptom of fibromyalgia was a symptom of hypothyroidism and vice versa.
He gives references for a vast number of them in:
Inadequate Thyroid Hormone Regulation as the Main Mechanism of Fibromyalgia: A Review of the Evidence
There were a couple of hypo symptoms (low basal temperature and low basal metabolic rate), which are arguably the characteristic symptoms of the disease, that hadn’t been documented in fibromyalgia. So he got a bunch of FMS patients and checked. And found them.
I really think that at this point, someone should be running a PCRT on ‘giving desiccated thyroid to FMS patients’! I would actually be surprised if T4 alone didn’t have some effect, but since Lowe thought (from extensive experience, but based on a sample that must have been skewed by people going to him after doctors failed to help) it was the least useful of all the thryoid hormone therapies, we should take him at his word and try desiccated thyroid. My own bet would be that T4/T3 in the same combination as secreted by the thyroid gland would be the best thing, but that’s just a detail.
Again, many thanks! I don’t want to have these beliefs if they’re false. Take me down.
It’s only mildly surprising that fibromyalgia patients have lower temperature in one study, or that improvement was seen in one study with thyroid hormone. Fibromyalgia patient’s having lower metabolic activity is a plausible component but does not necessarily implicate the thyroid. Taking anything with a stimulant effect would do similarly to thyroid hormone here.
People with fibromyalgia present similarly to patients with other chronic pain syndromes, and other presumed multifactorial syndromes like irritable bowel syndrome. It is associated with childhood trauma, sexual abuse, etc (just as is IBS) http://www.ncbi.nlm.nih.gov/pubmed/9407574
It’s likely a massive combination of metabolic, psychiatric/psychosonatic, social and physical factors at play here. That’s because the gestalt of the condition is that someone is complaining of pain that you can’t explain, which is apparent if you spend time seeing these people. Of course this is not going to be always caused by a problem in one hormonal controller of metabolism. Many (combinations of) problems can cause body pains!
I apologise that this note is less carefully proofed than previous ones but spending more time on this investigation does not seem likely to bear fruit.
Ryan, thank you, I really appreciate your time, and that is exactly the sort of thing that someone needs to say to me. I have come to the conclusion that I must be trolling.
My idea, which I have arrived at quite independently by a long chain of dodgy inferences from a minor puzzle to do with my own illness, it now seems to me can be summed up as:
Almost all the remaining unexplained human ailments can be explained as disorders of the endocrine system.
This idea seems to have been first thought of in the 1940s, and independently deduced, observed, or inferred many times since. If true, it would have a great number of disturbing implications. If untrue but widely believed, it would cause a catastrophe.
Now I look for them, there are published books suggesting this, and an entire tradition of alternative medicine based on it. Which reports success. But then, they would say that, wouldn’t they?
And yet no one except a few quacks believes it.
And so my mystery is now:
Where is the obvious refutation that means that it is false?
I apologise for wasting everyone’s time. I am not being sarcastic.
I realise that my argument is ‘You cannot prove me wrong, and therefore I must be right’
I realise just how bad that argument is.
I realise that I have blundered into a complicated subject that I am not in the least qualified to discuss.
I have already had to discard one simple obvious explanation for a complicated problem (they are almost always wrong). I do not like to believe in chocolate teapots.
I am asking for help in discarding another one.
What on earth is Less Wrong for, if it is not for this?
I do not imply that you must waste your time helping me. But I am damned sure that someone needs to say it plainly. It has fooled me. It is causing havoc. Why is it not true?
Where is the obvious refutation that means that it is false?
I think you’re underestimating the complexity of human biology.
The condition of a human body is a function of a very large number of factors: internal and external, somatic and psychological, genetic and acquired, etc. etc. Moreover, these factors are interdependent and tend to form feedback loops.
The situations where you have one clear cause for a problem certainly exist (e.g. infections, type 1 diabetes, etc.). But there are also situations where there are multiple factors in play. It would be a mistake either to believe that a single one of these factors explains everything, or to believe that this single factor is irrelevant, that is, “false”.
It is likely that some disorder of the hormonal system plays some role in some chronic illnesses for which we have no clear etiology. Can you fix those illnesses by tinkering with hormones? Maybe—that’s what medicine is trying to find out, with… various success so far.
Of course it’s complicated! I’m saying, there’s serious grounds for suspicion here. And the problem, if it exists at all, is likely to be gigantic. So we need to pay attention even though it doesn’t look very likely. A genuine Pascal’s Wager. We aren’t allowed to shrug our shoulders in response. Scope insensitivity is one of the sins.
All these funny diseases that look like mixtures of type 2 versions of well understood endocrine disorders. That I didn’t know about until after I’d made up the idea. And a very simple hypothesis that explains them all and should be easy to refute. I predict low body temperature in every different group. Patterns of differently low body temperatures correlating with how much the disease looks like classical hypothyroidism.
I have a hypothesis formed by whatever dodgy method I like, and which has turned out to have been commonly suspected by many different people, all starting from different observations, which I am now using to explain and predict lots of other facts that didn’t figure in the original making-it-up process.
Does the order in which I learned these facts matter? How should I adjust my conclusions to account, even given that I probably can’t remember the precise order? I am going through periods of puzzlement, enlightenment, and then spectacular rewards of confirmation followed by terror at the implications.
And the competing explanations all turn out to be philosophically suspect.
This science business turns out to be quite hard. And we claim (and I believe us) that we are unnaturally good at this sort of thing. Where have I erred, Brothers in Bayes?
What do you know that I don’t know? What conclusions (that are safe to draw in public) do you draw from my idea and do they turn out to be true? What are the odds and why? What is a yes worth. What is a no worth?
Are doctors actually trained to ignore these symptoms? Because they’re everywhere? How common are these diseases?
Are the patterns of occurrence the same in every racial group? Are they different in different countries? Are there places where some mysterious cause is making itself particularly obvious?
How much confounding has this caused in all epidemiological data ever? That might be the biggest prize.
Should I take my thoughts to medical statisticians? Or can I actually get a better answer here?
I’m saying, there’s serious grounds for suspicion here.
That’s still handwaving.
Let’s invoke Popper and ask for specific, testable, falsifiable statements. What exactly do you claim and want to test? What outcomes will prove you wrong? I don’t think the details of how you came to formulate your hypothesis matter.
Should I take my thoughts to medical statisticians?
We aren’t allowed to shrug our shoulders in response.
Actually we are. Changing the status quo is hard even if you are right.
Should I take my thoughts to medical statisticians? Or can I actually get a better answer here?
I don’t think mainling the original post to any medical statistician will get you anywhere. You would beforehand have to be clearer about your thesis and the evidence you have. It helps to cite the evidence.
which I am now using to explain and predict lots of other facts that didn’t figure in the original making-it-up process.
A prediction is something that has a credence value especially if you see yourself as Bayesian. At the moment you don’t state those.
Changing the status quo is hard even if you are right.
Shouldn’t be. If I can sharpen my argument to the point where I believe it myself, then I can take it to the ivory towers of the wise and they will listen. I know these people, and I trust them. They will do the right thing.
Excellent—thanks for responding to this so positively. I wouldn’t say you’re necessarily trolling, rather than just arguing a little more forcefully than someone else might.
Almost all the remaining unexplained human ailments can be explained as disorders of the endocrine system.
I basically think that this is the absurd conclusion that demonstrates your chain of reasoning to be false. This is far wronger than the idea that Fibromyalgia could have an endocrine cause. And I think you’ve identified this problem with your argument even more acutely that I had.
I think there are a lot of useful ways you can reason from here, such as:
1 - It has never been the case previously that almost all unexplained human ailments have shared a single simple explanation
2 - Many conditions that we discovered a long time ago had simpler ‘single pathogen’ explanations, whereas many newer ones are quite complex.
3 - Although many of these conditions will eventually be explained, the explanations are not likely to be visible to a non-expert.
4 - If they all shared an explanation, there’s no major reason why it should lie in the endocrine system. An alternative ‘catch-all’ explanation for these would be ‘psycho-neuro-immunology’, another somewhat overambitious school of mostly scientific thinking that could potentially claim these conditions more credibly.
My alternative explanation that collects this thinking is that most ‘unexplained human ailments’ are likely to be multifactorial. This is also the common wisdom. As to where to read and learn about this, by far the best place is www.uptodate.com. This is very popular but also potentially expensive. So if you really must, you could instead look through medical textbooks like Harrison’s or Kumar and Clarke, focussing specifically on unexplained conditions. I would warn that reading about conditions unexplained by medical science via textbooks of medical science might be a bit like pulling teeth, but truly it should be one way to abstract away the knowledge of these conditions.
Another approach might be to learn more about the scores of “medically unexplained physical symptoms”, “diagnoses of exclusion” and “functional disorders”. Likewise some “functional symptoms” and some “ideopathic” or “cryptogenic” conditions. “functional”, “ideopathic” and “cryptogenic” can be used interchangeably here, as in the sentence “we can’t explain your problem, but as a concession, let’s meet halfway and conceal our ignorance with this Latinate (or Greek) name. On my hypothesis, most such conditions will be about halfway heritable (as are most traits in behavioural genetics). They’ll be correlated with each other, and with mental health conditions. They’ll often be helped by SSRIs and by psychotherapy.
I guess you just have to learn a lot about these conditions with an open mind and see where you end up. If you gain a detailed knowledge and still think that some have an endocrine explanation, then write up your findings in a google doc, send it around to some other smart people who share that knowledge, and see what they say.
Ryan, thank you again. Your concerns are my concerns, I am grateful to you for them.
And I apologise. You have been talking to a raving lunatic, by the ICD10 diagnostic criteria as applied by my attorney and myself. See the exchange with buybuydandavis for details. I am apparently recovered now, in the opinion of one who should know.
I am painfully aware that I have reasoned myself into a place where I prove too much.
I am in the position of a philosopher who started out with a little detail, and is now claiming ‘It is at least marginally possible that here is the light and the sacred cup’. Knowing that he is wrong.
I was carefully and expensively trained to speak with certainty when and only when I was certain. The Lord knows I was never very good at it.
I have used plausible reasoning where I only trust classical logic.
I am forced to seek the Grail.
But I cannot shake the suspicion that I might be right. And I know that my hopeless hardware will not let me find the reason why I am wrong.
1 - It has never been the case previously that almost all unexplained human ailments have shared a single simple explanation
It has. The germ theory.
I am claiming that the great killers of the past may have left their shadows in our genes, and those shadows still plague us today.
I am claiming that the great changes we have made in our environment may have hurt us worse than we know.
Here I stand, naked to the world. Afraid. I can do no other in good conscience. I do not believe my own conclusion.
I hope that when I am shown to be wrong, I can retreat with no more than huge embarrassment, resolving to fail better next time.
And it all depends on the TSH test. If I am wrong about that, I am just wrong.
If the TSH test is flawed, then all our statistics are confounded, and we have some thinking to do.
Still Crocker’s Rules though! Let this cup pass from me!
OK, type 2 diabetics, suffering from a mysterious condition that prevents insulin (an endocrine hormone) acting on their cells, can achieve very good blood sugar control by overwhelming the resistance with exogenous insulin.
And yet they still suffer horrible complications. Which look awfully like hypothyroidism.
The simplest explanation is that this mysterious condition is interfering with other endocrine hormones as well.
Desiccated thyroid, containing excessive T3, will overwhelm the hormone resistance, and clear up the complications of diabetes.
T4 alone will not change the amount of T3 in the blood significantly, since it is subject to the body’s T4->T3 conversion mechanism, which defends T3 levels.
Therefore T4 will not help diabetics, but T4/T3 combinations will.
Broda Barnes observed this empirically in the sixties. I predicted it independently before I read his book.
Find a diabetic colleague, and explain this to him. I predict that he will suddenly take the idea very seriously indeed.
1 - It has never been the case previously that almost all unexplained human ailments have shared a single simple explanation
It has. The germ theory.
While I am very much not a medical professional, I do know that, while germs cause a lot of trouble, there are nonetheless quite a variety of things that can go wrong that have nothing to do with germs. There are even a lot of things that can go wrong that have nothing to do with the closely-related viruses.
Examples include:
Physical trauma (e.g. broken legs)
Nutritional deficiencies
Genetic diseases (sickle-cell anemia?)
Hormonal imbalances
Cancer (I think a growth is different from a germ, right?)
Asphyxiation and/or drowning
And I think it’s possible to cause trouble for yourself by drinking too much water as well—it has to be seriously too much—and that’s also not due to germs...
I know you’re teasing, but physical trauma and drowning aren’t unexplained, sickle-cell anaemia is very much explained by germ theory (malaria defense), controlling nutrition and energy usage is probably exactly what the thyroid system’s for in adults, hormonal imbalances are what I’m talking about, and OK, I’ll give you cancer. For now.
In fact I think I’m trying to add a coda to the germ theory. One reason that ancient control systems would just spontaneously go horribly wrong is if they were in a continuous state of desperate patching and hacking to deal with an intelligent and adaptive enemy. And pathogen evolution is just that.
That’s why we see in living systems a combination of beautiful engineering and idiotic kludge. Like a BMW with a tin can lid riveted on one side. The explanation is likely to do with bullets.
Therefore we expect infectious cause for this sort of horror. But we don’t find it. Where is it? In the past. Today’s fuckups are yesterday’s hastily constructed defenses.
Not of course to forget the environment. If we’ve got a hideously complicated and sensitive chemical control system that’s been tested to death really well in the presence of all the usual chemicals, and suddenly we start adding new chemicals, what then?
Notice that a lot of cancers are caused by novel chemicals, and a lot of them are caused by viruses.
Presumably all the viruses and bacteria and fungi and cancer cells are themselves generating novel chemicals in order to screw the system up so it can’t kill them.
One thing I don’t claim is vitamin deficiencies. But they fit into Cochran’s framework nicely.
And I’ll give you that if you deliberately drink far too much water even though you’d really like to stop and then it kills you, you’ve got a genuine ‘somatoform’ disorder.
Except even then. That sounds like the sort of thing people do on drugs. I wonder how those drugs act on the mind?
Sickle-cell anemia may have been a bad choice. It was supposed to be an example of genetic factors causing trouble—which can happen even in the complete absence of germs, since random mutations are rare but possible. (The fact that one particular genetic factor is partially successful because it provides a higher resistance to certain germs is somewhat beside the point).
Absolutely, a famous example is Queen Victoria’s mutation that caused haemophilia in some of her male descendants. The queen really does seem to have been the mutant, and it was just a rotten bit of luck!
What needs explanation is how a harmful random mutation can spread to a significant proportion of the population. One way that can happen is if it’s actually also a defence against something, and another is if the heterozygote version is good, but the homozygote is harmful.
With a large fitness advantage, mutations can spread quickly! Consider a lightning plague like the black death. It wiped out a third of the population of Europe in a couple of years, and then simmered and flared for centuries. A ‘harmful’ gene that defended against that would have had a whale of a time, and you’d expect to see it in all Europeans.
But if it’s really harmful, you’d expect that over the last 600 years, better defenses might have evolved, and the previous defence might start evolving back out.
About 500 years ago, all the old world plagues were introduced to the Americas at once, and they literally decimated the native population. I don’t know if there are any ‘pureblood’ native americans left, but if there are, their genes should be a mass of defensive scars.
What needs explanation is how a harmful random mutation can spread to a significant proportion of the population.
Easy.
The harm is easily avoided. For example, an allergy-against-bananas gene might not affect one’s reproductive fitness at all in the modern world—one merely needs to avoid bananas.
The “harm” is to the society, not to the individual. For example, a mutation (in males) that causes all children born to be male will not harm the person carrying the gene, but will end up with fewer total greeding pairs in subsequent generations.
A guy with the harmful mutation just happens to have a lot of wealth of political power—and takes a few dozen wives.
(1) Sure, but that sort of thing will just random-walk, it would take ages to go from one mutation to 50% of the population. It has almost no fitness effect. It will probably get gambler’s-ruined out.
(2) Absolutely, and we see those things in animals. You can evolve to extinction. In the particular case of a male-causing gene, I think it would have to stabilize very low (because the more successful it is the more harmful it is to the carrier) , but you can certainly imagine (and find) driving genes that just become rapidly prevalent and wipe out the species.
(3) Yes, but that’s just the random walk walking. It has to get very lucky to become prevalent, and if it’s actively harmful, it won’t get that lucky, and that will kill it off eventually.
In general, harmful mutations will die out. In order to spread to a significant proportion of the population, yes, a random mutation has to be lucky. It has to random-walk in a very rare way, and it is still more likely than not going to hit the gambler’s ruin and be eventually eliminated from the population, even if it first spreads to 99% of said population (an extremely unlikely event).
But the thing about random-walking is that it is random. One wouldn’t bet on a given harmful mutation spreading fast (not if one wanted to win the bet)… but if there are a million harmful mutations, then one of them could reasonably be expected to have one-in-a-million luck.
I think we’re pretty much on the same page. But have you actually calculated the odds? One in a million is no big deal. Twenty half-chances.
I must say I haven’t, and I don’t know how to (especially since it’s all screwed up by genes moving around and getting passed on together, and I don’t understand the first thing about all that). But it feels more like ‘thermodynamic entropy’ than ‘winning the lottery’.
Also remember that nothing is perfectly neutral. Even the banana man might get fed banana-cake by a dastardly enemy.
No, I haven’t actually calculated the odds. I wouldn’t really have much of an idea how. (I could probably work it out on a basis of—if a gene has x% chance of preventing descendants as compared to not having that gene and a y% chance of being passed on to any descendants—and then do some overly-simplified calculations from the values of x and y—but I haven’t, yet.)
Also remember that nothing is perfectly neutral. Even the banana man might get fed banana-cake by a dastardly enemy.
True, but his problem there isn’t the banana gene. His problem there is that he has a dastardly enemy. If he didn’t have the banana gene, the dastardly enemy could simply feed him arsenic cake instead, or just shoot him.
The official name of a mutation winning despite having no selection benefit is genetic drift. When I had genetics lessons in university the concept that was taught was that a significant amount of our genetic changes are due to gene drift but there’s no exact way to quantify how many.
Furthermore some genes aren’t stable and can easily mutate. Evolution doesn’t succeed in bringing color blindness to zero despite it being no useful mutation.
Yes, an obvious one is the inability to manufacture Vitamin C. Universal in great apes, including us, but every other animal and plant can do it, except guinea pigs.
I imagine that at some point our ancestors lived in a vitamin C rich environment, so losing this was no immediate handicap. But even then, the random drift should have taken ages. Is there some reason why losing this pathway would be a benefit?
Same for colour-blindness. Is it drifting, or is it actually good for something in an environment where it does no harm? (These poor children, none of them will ever be commercial pilots or qualified electricians....)
“Literally decimated” would have reduced the population by 10%. Some Native American groups were hit much harder than that. (I think the “mound builders” in what is now the southeastern US may have actually disappeared completely.)
Minus the “literally”, though, the word “decimated” in current English uses would include much more severe population declines. I’m just being unnecessarily pedantic.
Spectacular pedantry is sort of where I’m coming from here, though. And actually literally can be used metaphorically too, and has been for some centuries. I’m confidently expecting this to be the most controversial assertion in this entire discussion, so you can go look for your own references. [Openly trolling now]
According to Wikipedia, yes, the Norse made it to continental North America in pre-Columbian times and made multiple voyages there to obtain natural resources (primarily fur and timber), but did not establish any permanent colonies (perhaps due to hostile relations with the native Americans (which the Norse called the Skrælings)).
The Wikipedia article mentions that a Norwegian coin from King Olaf Kyrre’s reign (1067–1093) was allegedly found in a Native American archaeological site in the state of Maine, but does not mention any definitive evidence that the Norse made it to the mainland.
Tuberculosis keeps coming up. It was deadly and recent and widespread, and it’s implicated in the ‘plausible mechanism’ paper, and in the one about rheumatoid arthritis, and the other day I met an old friend with bladder cancer. Apparently he’s having tuberculosis drugs injected to try to kill it. No one knows why, but it works about 30% of the time!
It would be way interesting if someone had statistics for ancient diseases and statistics for modern unexplained diseases. I’ve no idea what to predict, but I bet it’s not ‘no correlation’.
Yes, I based the entire second post on it, and referenced it. But thanks, that would have been really useful!
I just emailed the address on the paper (paul ewald) to see what they thought of it. But no reply. If anyone knows one of them could you tell them there’s someone wrong on the internet?
I know you’re teasing, but physical trauma and drowning aren’t unexplained
Physical trauma doesn’t have to be explained, it’s an explanation. In cases like broken legs it’s a pretty straightforward explanation. In other cases like depression, it get’s more complicated.
An explanation is a chain of causal links, where each one is verified under interventions. If I hit you with a sledgehammer, your leg will break, and we know why, and it’s not that my anger causes ‘stress’, and that breaks your leg by magic stress-property, because I’m stressed too, and yet my leg never breaks.
A vague correlation is not an explanation. It’s a sign that you should look for one. Sure if I attacked you with a sledgehammer, you might get depressed. But why?
Sure if I attacked you with a sledgehammer, you might get depressed. But why?
Depression in patients with acute traumatic brain injury :
Major depression occurs in about one-quarter of patients after traumatic brain injury. This is the same frequency as in other major disorders such as stroke. Major depression appears to be provoked by one or more factors that include poor premorbid social functioning and previous psychiatric disorder or injury to certain critical brain locations.
Depression among older adults after traumatic brain injury: a national analysis.: TBI significantly increased the risk of depression among older adults, especially among men and those discharged to a skilled nursing facility. Results from this study will help increase awareness of the risk of depression post-TBI among older adults.
It’s plausible that the trauma kills neurons and thus creates depression. It’s also possible that some fascia tenses up and produces problems. It’s possible that it produces Sensor Motor Amnesia. It’s possible that it creates problematic inflammation.
There are a lot of plausible mechanisms to choose from.
Agreed. Thanks. It was more a sort of philosophical point about the nature of explanation. We might be able to tell which of these counted as an explanation by intervening later on in the proposed causal chain and seeing if the same results obtain.
As far as the philosophy goes, for most successful interventions in health care we don’t really know how they work.
Depression usually comes along with increased inflamation of the gut. Depression medicine that’s intented to target the brain because of chemical imbalance, also hit’s targets in the gut.
Does that mean I’m certain that those drugs fight depression by having positive effect on the gut? No, I’m not certain of that, but it’s an open possibility.
“Explanations” in general aren’t good at predicting outcomes for drugs. That way so many clinical trials fail. The only way that seems to work is to gather empiric evidence for treatments. That way you know whether the treatment works but not why it works.
Where is the obvious refutation that means that it is false?
90% of prospective drugs fail to produce positive clinical effects. That’s even through theoretically they should work.
The refutation comes with the clinical trial. That’s usually how it goes.
Absolutely. The only good evidence is randomized controlled trial. But what can we deduce using the bad evidence? Remember Amanda Knox. We showed she must be innocent by thinking. And everyone laughed at us for believing it. As if it was some sort of cult badge.
Drug trials are incredibly expensive. There’s a lot of money involved in reasoning about the likelihood that the drug will work before it’s put to trial. At the same time those people still often put their chips on drugs that turn out not to work.
That means that in many cases there’s not an obvious refutation to be found that a drug doesn’t work if you don’t actually run a trial.
And everyone laughed at us for believing it.
Who do you think laughed at us? As far as I understand the US media in general thought Know to be innocent and most people don’t care about the LW opinion on Amanda Knox.
I was reading RationalWiki about Less Wrong, to find out anything I should know about us, and they were in hilarious form about how the innocence of Amanda Knox was a compulsory belief.
So I thought “Oh, I didn’t realise we believed that.”. I’m British, and as you’d expect since the victim was British, the British press thought Amanda Knox was some sort of sexy cartwheeling antichristette. And went and read the article in question, which said: “Think about this as if it were a problem in probability.” So I did, for a couple of hours, and it was obvious that she was innocent.
So for a while I went around telling everyone that she was innocent, and they reacted how you’d expect when a middle aged man gets interested in the innocence of a pretty youngster.
And then it turned out she was, and they all think I’m a witch now.
And that is the first and only time I have seen this purported method work on something real. It works on made-up theoretical problems, Bob’s your uncle. And philosophically it’s nice.
But here we have a chance to find out something really important, or discredit something harmful. And then I’ll know. Both things.
Sometimes the answer is “You have no evidence”. (Or at least no good evidence.)
Of course, if you have no evidence that an accused criminal is guilty, you should assume they are innocent. But if you have no evidence in some medical theory, you shouldn’t be assuming the medical theory is true.
What on earth is Less Wrong for, if it is not for this?
I don’t think you are wrong to have this discussion on LW. The fact that the main post got 23 upvotes also indicates that the community doesn’t think you were wrong to post this here.
Now I look for them, there are published books suggesting this, and an entire tradition of alternative medicine based on it. Which reports success. But then, they would say that, wouldn’t they?
I think most illnesses are based on a chain of things going wrong with the body. Various alternative treatments do sometimes produce positive results. On the other hand they often don’t consistently produce results.
I think this too. I think the chain is (mysterious Cochran-type cause)->(mysterious endocrine transport disorder)->weird polymorphous syndrome.
We don’t find out this sort of thing by expensively trying random things. Especially since the tests are terrible. We have to work it out in theory, and then make predictions where we don’t already know the answers, and then see whether they’re true. And then adjust our beliefs.
If I am sounding like a fanatic, I hope it is a Bayesian fanatic. Because that is what I am. And here I have a chance to test my beliefs on something real, and hard. And I haven’t a clue how to go about doing it.
If I am sounding like a fanatic, I hope it is a Bayesian fanatic. Because that is what I am. And here I have a chance to test my beliefs. And I haven’t a clue how to go about doing it.
The start is getting clearer about your own theory and what you actually believe.
If you claim to be a Bayesian fanatic, then actually reason in probabilities. Bring numbers. Be clear about how probably you consider various thesis that you made.
Then it’s worth noting that you being right means that a company might make a billion dollars of that knowledge. Especially if the solution is a special mix of hormones that could be patented to make a synthetic analog of the pig thyroid.
That means that if you can convince the right person that there a 5% chance that you are right they might fund a 100,000$ trial to find out.
Just be to clear, I’m not a person who’s defending the status quo of the way the medical system works.
In the last month I sat down with a person who had a cat allergy and did an NLP intervention to treat it. The next day he spent 30 minutes with a cat to test and didn’t have any allergy symptoms. I put down 2:1 chances of success beforehand in our shared prediction database.
Next month I’m at a workshops with 3-4 QS people a 3-4 academic scientists to talk about what
I think the chain is (mysterious Cochran-type cause)->(mysterious endocrine transport disorder)->weird polymorphous syndrome.
Let’s say it’s: “A person shy’s away from conflicts that arise when they speak up. As a result the fascia around the throat is tense. The tense fascia then presses on the thyroid. The thyroid doesn’t work properly because there’s pressure on it. Badly regulated hormones then do a mess elsewhere in the body.”
In my understanding the recent history of hormone supplementation generally isn’t good, because the body stops to produce less of the hormone if it’s supplemented.
However let’s spend more time investigating it here. Alexandra Carmichael who used to be one of the people at the head of the Quantified Self mothership build CureTogether as a database where people can report their results with different treatments.
It has 137 treatments for Fibromyalgia. The most sensible treatments seem to be getting more sleep, resting and and hot bathes. But there are also drugs listed.
The first place is Low-Dose Naltrexone (LDN). Provided one doesn’t count the painkiller mariuanah, the second place as far as drug go goes to Thyroid hormone. In total it’s the 16 place in the list counting all other approaches.
That site’s a wonderful idea! And it looks as though LDN has some effect on the immune system.
So if we can trust it, it looks like the two things that attack the problem rather than the symptoms are LDN (suppresses immune reaction) and T3 (overwhelms my hypothesised immune-caused endocrine resistance).
This is the problem I keep having. Every time I see something new, it supports me. Can anyone find something that I can’t explain?
And just for the avoidance of doubt, I think taking pure T3 is a terrible idea. But John Lowe thought it worked for him and for many of his patients, and I trust John Lowe much more than I trust myself.
I don’t think I’m conflating something in the context of this discussion. I think johnlawrenceaspden does focus on providing a plausible narrative instead of making falsifiable statements.
Is fair, but surely those predictions can be about bits of the medical literature that I haven’t seen yet, or haven’t understood properly, otherwise history would not be a rational endeavour.
Where is the obvious refutation that means that it is false?
You admitted it yourself. You’re using dodgy inferences!
This is especially bad if you have a chain of them, as the errors accumulate—if your reasoning depends on five dodgy inferences each with a 60% chance of being correct, you’re already down to 8%.
Right! So now I have an 8% chance of being right about something really serious. And so I need to make a prediction and work out whether it’s true, and then adjust. You try it!
What kind of prediction could you possibly make about “almost all the remaining unexplained human ailments”, that could be checked to see if it’s true?
And even if there was something, you haven’t actually made or tested the prediction yet. So not only have you used dodgy inferences, you’re putting the burden of proof on the wrong side. It’s not up to other people to prove it false, it’s up to you to prove it true, and if you haven’t done that yet, you have no business believing it.
(a) Actually, my wonderful GP confirms that whatever phrasing he uses, the local lab won’t test FT4 unless TSH is abnormal. He’s going to try ‘FT4 IRRESPECTIVE of TSH result’ and see what happens. Of course, this is England, and you may have a different experience. The T4 tests are badly standardized, apparently you can get high FT4 by one method and low FT4 by another from the same blood sample. I don’t think they’ve ever been used for anything serious since TSH is a better test anyway, so the lab may not be acting insanely here.
I’ve only skimmed this but let me give a bunch of info that seems relevant. (As I understand it, the question is whether low thyroid levels could cause chronic fatigue and fibromyalgia). For background, I am a junior doctor with no specific experience in endocrinology and support healthy scepticism towards the medical establishment:
Thyroid hormones are of course the first thing that one thinks of in people with low mood. Sometimes one will check the T4 and T3 as well as the TSH.
it is also one of the first things that one would research and it looks like there are plenty of papers checking hormone levels in these conditions.
People with hypothyroidism usually have high TSH. It would be surprising if this was different for people with fibromyalgia unless they had a specific insensitivity to thyroid hormone, which seems like a different hypothesis.
people with hypothyroidism usually don’t complain of pains in the same way as people with fibromyalgia.
people with fibromyalgia usually have a high sensitivity to slight painful stimuli in a way that I’ve never seen from people with hypothyroidism.
I also must admit that the since the post seems to me to be not just wrong but also very slow-moving, I haven’t read all of it. I would suggest rewriting this in a few paragraphs with citations to get feedback on a more brief version.
A likelier solution would be that pain-sensitivity and vulnerability to demotivation and fatigue are just (mostly additive) polygenic traits. Look to partially confirm this in 0-5 years when the first GWAS come out and demonstrate that thousands of genes make these diseases more likely, similarly to IQ and height.
I just stumbled across this and see it is in fact 5 years later! Have you seen anything interesting from GWAS so far?
Hi Ryan, thanks. My point is that ‘hypothyroidism’ is defined by high TSH. I wonder if it’s possible to have ‘hypometabolism’ or ‘all the symptoms of hypothyroidism’ whilst having a normal or even low TSH and maybe normal levels of the blood hormones too.
to answer your points:
(a) Yes, agreed. Only wrinkle here is that labs often refuse to check T4 if TSH is normal. This has happened to me twice despite my doctor specifically requesting an FT4 test. And I personally know someone who had CFS for years and lots of expensive NHS and BUPA and privately paid treatment without any thyroid test except for TSH.
(b) Yes, but if you’ve already removed all the people with strange hormone levels (because they’re hypothyroid, and so they don’t have CFS or FMS), then of course you’ll find normal levels in the remaining cases.
(c) Agreed, because hypothyroidism is defined by TSH. My hypothesis is exactly that many cases of FMS/CFS are ‘something wrong with the thyroid system that doesn’t show up on laboratory hormone level tests’.
(d) Hypothyroidism has lots of famously non-specific symptoms. Do hypothyroid patients sometimes complain of pains in the same way?
(e) that’s interesting and surprises me. I was under the impression that exactly that kind of widespread pain was one of the (many possible) symptoms of hypothyroidism. I’ll go and look.
Thanks ever so! I’ve added the explicit hypothesis to the summary. I’ll go and see what I can find out about pain in hypothyroidism/fibromyalgia.
a) This is a bit misleading. I’ve never had a lab refuse to do any test as simple as T4. It’s more a matter of how you communicate it. If you as for “thyroid function tests” or “TSH, T3, T4″ without clearly explaining, then they will usually stop at a normal TSH.
b) Most people diagnosed with CFS have had their thyroid levels checked but is this necessarily so for fibromyalgia? I don’t think so. Also there are studies where they stimulate release of thyroid humans. There are literally hundreds of highly relevant studies here.
c) Aren’t there things like thyroid receptor abnormalities that have different biochemistry but similar presentation to hypothyroidism? (And wildly different to fibromyalgia?) One has to look into this.
d) usually it’s just tiredness and slowness isn’t it? The fact that hypothyroidism presents so generally actually makes it less likely, not more likely to bear a specific connection here.
e) people with fibromyalgia often recoil if you try to examine them, take blood etc in a trait that they largely share with people who are anxious or have mental health issues with psychosomatic complaints.
What is needed here are similarities that are specific to these conditions and that are shared, whereas here it is the aspects that are the most general that are shared but the main facets of each condition are quite different and overall the two conditions don’t blur together in an interesting way.
At the fourth attempt, my doctor managed to get the local lab to test TSH,T3 and T4 simultaneously. He had to ring them up and ask them in person, apparently. It turns out that I’ve currently got TSH~2.5, and FT4,FT3 low-in-range. Given that that looks like central hypothyroidism, and that’s under the influence of 1 grain/day of desiccated thyroid, we’ve decided we that we have no clue, and I’m carrying on messing around with random thyroid drugs aiming for relief of symptoms (which are all gone, but I keep having to up the dose to keep it so).
Basically Christ knows. If I’m not medically unique, there’s something very funny going on.
Aren’t you just taking thyroid hormones analogues (not T3/T4) that are—as expected—suppressing the pituitary production of TSH?
That’s what I was expecting, but 2.5 isn’t suppressed, it’s actually quite high compared to the average for healthy people, (or at least normal, depending on what you think normal is). And roughly the same as it was at the start of all this. And both the free hormones look low. You’d think adding a fair bit of thyroid to a healthy system would have bumped up the free hormones and maybe lowered TSH to somewhere like the hyperthyroid range.
What’s really weird is that I’ve tripled the dose of NDT since the last time I had blood drawn, and my TSH has gone up slightly in response. I thought I’d be seriously suppressing my own system by now.
It’s possible that I’ve just developed a primary gland failure, but that’s weird because there was no sign of it when I first showed severe symptoms.
Ok so your TSH is normal and your T3/T4 are low in the normal range because you’ve replaced them with some T1/T2. Every value is in the normal range. Problem?
It makes no sense at all to call it pituitary failure (central hypothyroidism) - that would imply low TSH. You could argue that it’s successfully medicated peripheral hypothyroidism if anything, though that’s a stretch.
Ryan, this is great, I came here for an argument! Thanks. (“I wish to believe ‘snow is blue’ if and only if snow is blue”)
(a) OK, can we agree on “In most cases with ‘normal’ 0.3<TSH<5.5, TSH is the sole test performed”?
(b1) I don’t know, but given that FMS includes ‘brain fog’ and ‘tiredness’ I’d be surprised if many people with it haven’t had a TSH test. I would be surprised by the existence of people who only have the tender points and no other hypometabolic symptoms. Do we know what proportion that is?
(b2) “Also there are studies where they stimulate release of thyroid humans. There are literally hundreds of highly relevant studies here.” I don’t quite understand what you’re saying here. Can you link to a couple? Google scholar “fibromyalgia and thyroid” gives top hit: http://europepmc.org/abstract/med/1512769, Neeck G , Riedel W “Thyroid function in patients with fibromyalgia syndrome.”, in which they find abnormalities in a thyroid hormone releasing test in fibromyalgia patients. Doesn’t that support me?
(c) There are forms of hypothyroidism that don’t show up on the TSH test certainly, ‘central hypothyroidism’ and ‘peripheral resistance to thyroid hormone’, which have the same presentation but normal TSH. ‘Central’ should give you normal TSH but low T4 and T3. ‘Peripheral’ should be normal in all respects. But they’re thought to be vanishingly rare, and as far as I know, CFS/FMS people aren’t tested for them. In fact presumably the only way to test for them would be a trial of thyroid hormones! That’s kind of my point.
(d) Not just tiredness and slowness. It’s more of a general metabolic collapse. And which systems fail first seems to be random, which is why it’s so difficult to diagnose clinically.
(e) I’d expect anyone with widespread pain to recoil if you tried to touch them.
“What is needed here are similarities that are specific to these conditions and that are shared, whereas here it is the aspects that are the most general that are shared but the main facets of each condition are quite different and overall the two conditions don’t blur together in an interesting way.”
John Lowe appears to have known the rheumatology and endocrinology literature backwards, and claimed that every symptom of fibromyalgia was a symptom of hypothyroidism and vice versa.
He gives references for a vast number of them in:
Inadequate Thyroid Hormone Regulation as the Main Mechanism of Fibromyalgia: A Review of the Evidence
You can find it here: http://tpauk.com/main/dr-john-lowe-overview-of-important-articles/
There were a couple of hypo symptoms (low basal temperature and low basal metabolic rate), which are arguably the characteristic symptoms of the disease, that hadn’t been documented in fibromyalgia. So he got a bunch of FMS patients and checked. And found them.
I really think that at this point, someone should be running a PCRT on ‘giving desiccated thyroid to FMS patients’! I would actually be surprised if T4 alone didn’t have some effect, but since Lowe thought (from extensive experience, but based on a sample that must have been skewed by people going to him after doctors failed to help) it was the least useful of all the thryoid hormone therapies, we should take him at his word and try desiccated thyroid. My own bet would be that T4/T3 in the same combination as secreted by the thyroid gland would be the best thing, but that’s just a detail.
Again, many thanks! I don’t want to have these beliefs if they’re false. Take me down.
Sorry this discussion is not interesting to me.
It’s only mildly surprising that fibromyalgia patients have lower temperature in one study, or that improvement was seen in one study with thyroid hormone. Fibromyalgia patient’s having lower metabolic activity is a plausible component but does not necessarily implicate the thyroid. Taking anything with a stimulant effect would do similarly to thyroid hormone here.
People with fibromyalgia present similarly to patients with other chronic pain syndromes, and other presumed multifactorial syndromes like irritable bowel syndrome. It is associated with childhood trauma, sexual abuse, etc (just as is IBS) http://www.ncbi.nlm.nih.gov/pubmed/9407574
It’s likely a massive combination of metabolic, psychiatric/psychosonatic, social and physical factors at play here. That’s because the gestalt of the condition is that someone is complaining of pain that you can’t explain, which is apparent if you spend time seeing these people. Of course this is not going to be always caused by a problem in one hormonal controller of metabolism. Many (combinations of) problems can cause body pains!
I apologise that this note is less carefully proofed than previous ones but spending more time on this investigation does not seem likely to bear fruit.
Ryan, thank you, I really appreciate your time, and that is exactly the sort of thing that someone needs to say to me. I have come to the conclusion that I must be trolling.
My idea, which I have arrived at quite independently by a long chain of dodgy inferences from a minor puzzle to do with my own illness, it now seems to me can be summed up as:
Almost all the remaining unexplained human ailments can be explained as disorders of the endocrine system.
This idea seems to have been first thought of in the 1940s, and independently deduced, observed, or inferred many times since. If true, it would have a great number of disturbing implications. If untrue but widely believed, it would cause a catastrophe.
Now I look for them, there are published books suggesting this, and an entire tradition of alternative medicine based on it. Which reports success. But then, they would say that, wouldn’t they?
And yet no one except a few quacks believes it.
And so my mystery is now:
Where is the obvious refutation that means that it is false?
I apologise for wasting everyone’s time. I am not being sarcastic.
I realise that my argument is ‘You cannot prove me wrong, and therefore I must be right’
I realise just how bad that argument is.
I realise that I have blundered into a complicated subject that I am not in the least qualified to discuss.
I have already had to discard one simple obvious explanation for a complicated problem (they are almost always wrong). I do not like to believe in chocolate teapots.
I am asking for help in discarding another one.
What on earth is Less Wrong for, if it is not for this?
I do not imply that you must waste your time helping me. But I am damned sure that someone needs to say it plainly. It has fooled me. It is causing havoc. Why is it not true?
I think you’re underestimating the complexity of human biology.
The condition of a human body is a function of a very large number of factors: internal and external, somatic and psychological, genetic and acquired, etc. etc. Moreover, these factors are interdependent and tend to form feedback loops.
The situations where you have one clear cause for a problem certainly exist (e.g. infections, type 1 diabetes, etc.). But there are also situations where there are multiple factors in play. It would be a mistake either to believe that a single one of these factors explains everything, or to believe that this single factor is irrelevant, that is, “false”.
It is likely that some disorder of the hormonal system plays some role in some chronic illnesses for which we have no clear etiology. Can you fix those illnesses by tinkering with hormones? Maybe—that’s what medicine is trying to find out, with… various success so far.
tl;dr: It’s complicated :-)
Of course it’s complicated! I’m saying, there’s serious grounds for suspicion here. And the problem, if it exists at all, is likely to be gigantic. So we need to pay attention even though it doesn’t look very likely. A genuine Pascal’s Wager. We aren’t allowed to shrug our shoulders in response. Scope insensitivity is one of the sins.
All these funny diseases that look like mixtures of type 2 versions of well understood endocrine disorders. That I didn’t know about until after I’d made up the idea. And a very simple hypothesis that explains them all and should be easy to refute. I predict low body temperature in every different group. Patterns of differently low body temperatures correlating with how much the disease looks like classical hypothyroidism.
I have a hypothesis formed by whatever dodgy method I like, and which has turned out to have been commonly suspected by many different people, all starting from different observations, which I am now using to explain and predict lots of other facts that didn’t figure in the original making-it-up process.
Does the order in which I learned these facts matter? How should I adjust my conclusions to account, even given that I probably can’t remember the precise order? I am going through periods of puzzlement, enlightenment, and then spectacular rewards of confirmation followed by terror at the implications.
And the competing explanations all turn out to be philosophically suspect.
This science business turns out to be quite hard. And we claim (and I believe us) that we are unnaturally good at this sort of thing. Where have I erred, Brothers in Bayes?
What do you know that I don’t know? What conclusions (that are safe to draw in public) do you draw from my idea and do they turn out to be true? What are the odds and why? What is a yes worth. What is a no worth?
Are doctors actually trained to ignore these symptoms? Because they’re everywhere? How common are these diseases?
Are the patterns of occurrence the same in every racial group? Are they different in different countries? Are there places where some mysterious cause is making itself particularly obvious?
How much confounding has this caused in all epidemiological data ever? That might be the biggest prize.
Should I take my thoughts to medical statisticians? Or can I actually get a better answer here?
That’s still handwaving.
Let’s invoke Popper and ask for specific, testable, falsifiable statements. What exactly do you claim and want to test? What outcomes will prove you wrong? I don’t think the details of how you came to formulate your hypothesis matter.
Will they listen to you?
http://lesswrong.com/lw/nbm/thyroid_hormones_chronic_fatigue_and_fibromyalgia/
I hope so!
Actually we are. Changing the status quo is hard even if you are right.
I don’t think mainling the original post to any medical statistician will get you anywhere. You would beforehand have to be clearer about your thesis and the evidence you have. It helps to cite the evidence.
A prediction is something that has a credence value especially if you see yourself as Bayesian. At the moment you don’t state those.
Shouldn’t be. If I can sharpen my argument to the point where I believe it myself, then I can take it to the ivory towers of the wise and they will listen. I know these people, and I trust them. They will do the right thing.
For the rest, see:
http://lesswrong.com/lw/nbm/thyroid_hormones_chronic_fatigue_and_fibromyalgia/
How much have you talked to people inside the system? From my conversations with stakeholders I have the impression that change is very hard.
Excellent—thanks for responding to this so positively. I wouldn’t say you’re necessarily trolling, rather than just arguing a little more forcefully than someone else might.
I basically think that this is the absurd conclusion that demonstrates your chain of reasoning to be false. This is far wronger than the idea that Fibromyalgia could have an endocrine cause. And I think you’ve identified this problem with your argument even more acutely that I had.
I think there are a lot of useful ways you can reason from here, such as: 1 - It has never been the case previously that almost all unexplained human ailments have shared a single simple explanation 2 - Many conditions that we discovered a long time ago had simpler ‘single pathogen’ explanations, whereas many newer ones are quite complex. 3 - Although many of these conditions will eventually be explained, the explanations are not likely to be visible to a non-expert. 4 - If they all shared an explanation, there’s no major reason why it should lie in the endocrine system. An alternative ‘catch-all’ explanation for these would be ‘psycho-neuro-immunology’, another somewhat overambitious school of mostly scientific thinking that could potentially claim these conditions more credibly.
My alternative explanation that collects this thinking is that most ‘unexplained human ailments’ are likely to be multifactorial. This is also the common wisdom. As to where to read and learn about this, by far the best place is www.uptodate.com. This is very popular but also potentially expensive. So if you really must, you could instead look through medical textbooks like Harrison’s or Kumar and Clarke, focussing specifically on unexplained conditions. I would warn that reading about conditions unexplained by medical science via textbooks of medical science might be a bit like pulling teeth, but truly it should be one way to abstract away the knowledge of these conditions.
Another approach might be to learn more about the scores of “medically unexplained physical symptoms”, “diagnoses of exclusion” and “functional disorders”. Likewise some “functional symptoms” and some “ideopathic” or “cryptogenic” conditions. “functional”, “ideopathic” and “cryptogenic” can be used interchangeably here, as in the sentence “we can’t explain your problem, but as a concession, let’s meet halfway and conceal our ignorance with this Latinate (or Greek) name. On my hypothesis, most such conditions will be about halfway heritable (as are most traits in behavioural genetics). They’ll be correlated with each other, and with mental health conditions. They’ll often be helped by SSRIs and by psychotherapy.
I guess you just have to learn a lot about these conditions with an open mind and see where you end up. If you gain a detailed knowledge and still think that some have an endocrine explanation, then write up your findings in a google doc, send it around to some other smart people who share that knowledge, and see what they say.
Ryan, thank you again. Your concerns are my concerns, I am grateful to you for them.
And I apologise. You have been talking to a raving lunatic, by the ICD10 diagnostic criteria as applied by my attorney and myself. See the exchange with buybuydandavis for details. I am apparently recovered now, in the opinion of one who should know.
I am painfully aware that I have reasoned myself into a place where I prove too much.
I am in the position of a philosopher who started out with a little detail, and is now claiming ‘It is at least marginally possible that here is the light and the sacred cup’. Knowing that he is wrong.
I was carefully and expensively trained to speak with certainty when and only when I was certain. The Lord knows I was never very good at it.
I have used plausible reasoning where I only trust classical logic.
I am forced to seek the Grail.
But I cannot shake the suspicion that I might be right. And I know that my hopeless hardware will not let me find the reason why I am wrong.
It has. The germ theory.
I am claiming that the great killers of the past may have left their shadows in our genes, and those shadows still plague us today.
I am claiming that the great changes we have made in our environment may have hurt us worse than we know.
Here I stand, naked to the world. Afraid. I can do no other in good conscience. I do not believe my own conclusion.
I hope that when I am shown to be wrong, I can retreat with no more than huge embarrassment, resolving to fail better next time.
And it all depends on the TSH test. If I am wrong about that, I am just wrong.
If the TSH test is flawed, then all our statistics are confounded, and we have some thinking to do.
Still Crocker’s Rules though! Let this cup pass from me!
Forget about being proved wrong and facing huge embarassment.
Short-circuit that by getting some background domain knowledge then making claims that in light of that knowledge are reasonable.
OK, type 2 diabetics, suffering from a mysterious condition that prevents insulin (an endocrine hormone) acting on their cells, can achieve very good blood sugar control by overwhelming the resistance with exogenous insulin.
And yet they still suffer horrible complications. Which look awfully like hypothyroidism.
The simplest explanation is that this mysterious condition is interfering with other endocrine hormones as well.
Desiccated thyroid, containing excessive T3, will overwhelm the hormone resistance, and clear up the complications of diabetes.
T4 alone will not change the amount of T3 in the blood significantly, since it is subject to the body’s T4->T3 conversion mechanism, which defends T3 levels.
Therefore T4 will not help diabetics, but T4/T3 combinations will.
Broda Barnes observed this empirically in the sixties. I predicted it independently before I read his book.
Find a diabetic colleague, and explain this to him. I predict that he will suddenly take the idea very seriously indeed.
While I am very much not a medical professional, I do know that, while germs cause a lot of trouble, there are nonetheless quite a variety of things that can go wrong that have nothing to do with germs. There are even a lot of things that can go wrong that have nothing to do with the closely-related viruses.
Examples include:
Physical trauma (e.g. broken legs)
Nutritional deficiencies
Genetic diseases (sickle-cell anemia?)
Hormonal imbalances
Cancer (I think a growth is different from a germ, right?)
Asphyxiation and/or drowning
And I think it’s possible to cause trouble for yourself by drinking too much water as well—it has to be seriously too much—and that’s also not due to germs...
I know you’re teasing, but physical trauma and drowning aren’t unexplained, sickle-cell anaemia is very much explained by germ theory (malaria defense), controlling nutrition and energy usage is probably exactly what the thyroid system’s for in adults, hormonal imbalances are what I’m talking about, and OK, I’ll give you cancer. For now.
In fact I think I’m trying to add a coda to the germ theory. One reason that ancient control systems would just spontaneously go horribly wrong is if they were in a continuous state of desperate patching and hacking to deal with an intelligent and adaptive enemy. And pathogen evolution is just that.
That’s why we see in living systems a combination of beautiful engineering and idiotic kludge. Like a BMW with a tin can lid riveted on one side. The explanation is likely to do with bullets.
Therefore we expect infectious cause for this sort of horror. But we don’t find it. Where is it? In the past. Today’s fuckups are yesterday’s hastily constructed defenses.
Not of course to forget the environment. If we’ve got a hideously complicated and sensitive chemical control system that’s been tested to death really well in the presence of all the usual chemicals, and suddenly we start adding new chemicals, what then?
Notice that a lot of cancers are caused by novel chemicals, and a lot of them are caused by viruses.
Presumably all the viruses and bacteria and fungi and cancer cells are themselves generating novel chemicals in order to screw the system up so it can’t kill them.
I’m not saying. I’m just saying....
Infectious cause, immune defence, recent environmental change, recent adaptation to environmental change.
The four horsemen of unexplained diseases.
One thing I don’t claim is vitamin deficiencies. But they fit into Cochran’s framework nicely.
And I’ll give you that if you deliberately drink far too much water even though you’d really like to stop and then it kills you, you’ve got a genuine ‘somatoform’ disorder.
Except even then. That sounds like the sort of thing people do on drugs. I wonder how those drugs act on the mind?
Sickle-cell anemia may have been a bad choice. It was supposed to be an example of genetic factors causing trouble—which can happen even in the complete absence of germs, since random mutations are rare but possible. (The fact that one particular genetic factor is partially successful because it provides a higher resistance to certain germs is somewhat beside the point).
Absolutely, a famous example is Queen Victoria’s mutation that caused haemophilia in some of her male descendants. The queen really does seem to have been the mutant, and it was just a rotten bit of luck!
What needs explanation is how a harmful random mutation can spread to a significant proportion of the population. One way that can happen is if it’s actually also a defence against something, and another is if the heterozygote version is good, but the homozygote is harmful.
With a large fitness advantage, mutations can spread quickly! Consider a lightning plague like the black death. It wiped out a third of the population of Europe in a couple of years, and then simmered and flared for centuries. A ‘harmful’ gene that defended against that would have had a whale of a time, and you’d expect to see it in all Europeans.
But if it’s really harmful, you’d expect that over the last 600 years, better defenses might have evolved, and the previous defence might start evolving back out.
About 500 years ago, all the old world plagues were introduced to the Americas at once, and they literally decimated the native population. I don’t know if there are any ‘pureblood’ native americans left, but if there are, their genes should be a mass of defensive scars.
Easy.
The harm is easily avoided. For example, an allergy-against-bananas gene might not affect one’s reproductive fitness at all in the modern world—one merely needs to avoid bananas.
The “harm” is to the society, not to the individual. For example, a mutation (in males) that causes all children born to be male will not harm the person carrying the gene, but will end up with fewer total greeding pairs in subsequent generations.
A guy with the harmful mutation just happens to have a lot of wealth of political power—and takes a few dozen wives.
(1) Sure, but that sort of thing will just random-walk, it would take ages to go from one mutation to 50% of the population. It has almost no fitness effect. It will probably get gambler’s-ruined out.
(2) Absolutely, and we see those things in animals. You can evolve to extinction. In the particular case of a male-causing gene, I think it would have to stabilize very low (because the more successful it is the more harmful it is to the carrier) , but you can certainly imagine (and find) driving genes that just become rapidly prevalent and wipe out the species.
(3) Yes, but that’s just the random walk walking. It has to get very lucky to become prevalent, and if it’s actively harmful, it won’t get that lucky, and that will kill it off eventually.
A mutation needs an edge to spread fast.
In general, harmful mutations will die out. In order to spread to a significant proportion of the population, yes, a random mutation has to be lucky. It has to random-walk in a very rare way, and it is still more likely than not going to hit the gambler’s ruin and be eventually eliminated from the population, even if it first spreads to 99% of said population (an extremely unlikely event).
But the thing about random-walking is that it is random. One wouldn’t bet on a given harmful mutation spreading fast (not if one wanted to win the bet)… but if there are a million harmful mutations, then one of them could reasonably be expected to have one-in-a-million luck.
I think we’re pretty much on the same page. But have you actually calculated the odds? One in a million is no big deal. Twenty half-chances.
I must say I haven’t, and I don’t know how to (especially since it’s all screwed up by genes moving around and getting passed on together, and I don’t understand the first thing about all that). But it feels more like ‘thermodynamic entropy’ than ‘winning the lottery’.
Also remember that nothing is perfectly neutral. Even the banana man might get fed banana-cake by a dastardly enemy.
No, I haven’t actually calculated the odds. I wouldn’t really have much of an idea how. (I could probably work it out on a basis of—if a gene has x% chance of preventing descendants as compared to not having that gene and a y% chance of being passed on to any descendants—and then do some overly-simplified calculations from the values of x and y—but I haven’t, yet.)
True, but his problem there isn’t the banana gene. His problem there is that he has a dastardly enemy. If he didn’t have the banana gene, the dastardly enemy could simply feed him arsenic cake instead, or just shoot him.
The official name of a mutation winning despite having no selection benefit is genetic drift. When I had genetics lessons in university the concept that was taught was that a significant amount of our genetic changes are due to gene drift but there’s no exact way to quantify how many.
Furthermore some genes aren’t stable and can easily mutate. Evolution doesn’t succeed in bringing color blindness to zero despite it being no useful mutation.
Yes, an obvious one is the inability to manufacture Vitamin C. Universal in great apes, including us, but every other animal and plant can do it, except guinea pigs.
I imagine that at some point our ancestors lived in a vitamin C rich environment, so losing this was no immediate handicap. But even then, the random drift should have taken ages. Is there some reason why losing this pathway would be a benefit?
Same for colour-blindness. Is it drifting, or is it actually good for something in an environment where it does no harm? (These poor children, none of them will ever be commercial pilots or qualified electricians....)
“Literally decimated” would have reduced the population by 10%. Some Native American groups were hit much harder than that. (I think the “mound builders” in what is now the southeastern US may have actually disappeared completely.)
Accepted. I have managed to use decimated in the wrong way. Sorry.
Minus the “literally”, though, the word “decimated” in current English uses would include much more severe population declines. I’m just being unnecessarily pedantic.
Spectacular pedantry is sort of where I’m coming from here, though. And actually literally can be used metaphorically too, and has been for some centuries. I’m confidently expecting this to be the most controversial assertion in this entire discussion, so you can go look for your own references. [Openly trolling now]
In fact, how did any of them live through that? Did the vikings take some diseases and some genes over with them early doors?
Did the Vikings ever get out of Newfoundland? Is there any evidence they made it to the mainland?
According to Wikipedia, yes, the Norse made it to continental North America in pre-Columbian times and made multiple voyages there to obtain natural resources (primarily fur and timber), but did not establish any permanent colonies (perhaps due to hostile relations with the native Americans (which the Norse called the Skrælings)).
I asked about the mainland. The Vikings made it to Newfoundland, certainly, but Newfoundland is an island.
The Wikipedia article mentions that a Norwegian coin from King Olaf Kyrre’s reign (1067–1093) was allegedly found in a Native American archaeological site in the state of Maine, but does not mention any definitive evidence that the Norse made it to the mainland.
Yes, I know. That’s why I asked :-/
I have no clue. Is there a vikingologist in the house?
Tuberculosis keeps coming up. It was deadly and recent and widespread, and it’s implicated in the ‘plausible mechanism’ paper, and in the one about rheumatoid arthritis, and the other day I met an old friend with bladder cancer. Apparently he’s having tuberculosis drugs injected to try to kill it. No one knows why, but it works about 30% of the time!
It would be way interesting if someone had statistics for ancient diseases and statistics for modern unexplained diseases. I’ve no idea what to predict, but I bet it’s not ‘no correlation’.
Have you seen Greg Cochran’s paper on infections?
Yes, I based the entire second post on it, and referenced it. But thanks, that would have been really useful!
I just emailed the address on the paper (paul ewald) to see what they thought of it. But no reply. If anyone knows one of them could you tell them there’s someone wrong on the internet?
Physical trauma doesn’t have to be explained, it’s an explanation. In cases like broken legs it’s a pretty straightforward explanation. In other cases like depression, it get’s more complicated.
An explanation is a chain of causal links, where each one is verified under interventions. If I hit you with a sledgehammer, your leg will break, and we know why, and it’s not that my anger causes ‘stress’, and that breaks your leg by magic stress-property, because I’m stressed too, and yet my leg never breaks.
A vague correlation is not an explanation. It’s a sign that you should look for one. Sure if I attacked you with a sledgehammer, you might get depressed. But why?
Depression in patients with acute traumatic brain injury :
Major depression occurs in about one-quarter of patients after traumatic brain injury. This is the same frequency as in other major disorders such as stroke. Major depression appears to be provoked by one or more factors that include poor premorbid social functioning and previous psychiatric disorder or injury to certain critical brain locations.Depression among older adults after traumatic brain injury: a national analysis.:
TBI significantly increased the risk of depression among older adults, especially among men and those discharged to a skilled nursing facility. Results from this study will help increase awareness of the risk of depression post-TBI among older adults.It’s plausible that the trauma kills neurons and thus creates depression. It’s also possible that some fascia tenses up and produces problems. It’s possible that it produces Sensor Motor Amnesia. It’s possible that it creates problematic inflammation.
There are a lot of plausible mechanisms to choose from.
Agreed. Thanks. It was more a sort of philosophical point about the nature of explanation. We might be able to tell which of these counted as an explanation by intervening later on in the proposed causal chain and seeing if the same results obtain.
As far as the philosophy goes, for most successful interventions in health care we don’t really know how they work.
Depression usually comes along with increased inflamation of the gut. Depression medicine that’s intented to target the brain because of chemical imbalance, also hit’s targets in the gut.
Does that mean I’m certain that those drugs fight depression by having positive effect on the gut? No, I’m not certain of that, but it’s an open possibility.
“Explanations” in general aren’t good at predicting outcomes for drugs. That way so many clinical trials fail. The only way that seems to work is to gather empiric evidence for treatments. That way you know whether the treatment works but not why it works.
Trolling or eyerolling? You decide!
X-D
90% of prospective drugs fail to produce positive clinical effects. That’s even through theoretically they should work. The refutation comes with the clinical trial. That’s usually how it goes.
Absolutely. The only good evidence is randomized controlled trial. But what can we deduce using the bad evidence? Remember Amanda Knox. We showed she must be innocent by thinking. And everyone laughed at us for believing it. As if it was some sort of cult badge.
Drug trials are incredibly expensive. There’s a lot of money involved in reasoning about the likelihood that the drug will work before it’s put to trial. At the same time those people still often put their chips on drugs that turn out not to work.
That means that in many cases there’s not an obvious refutation to be found that a drug doesn’t work if you don’t actually run a trial.
Who do you think laughed at us? As far as I understand the US media in general thought Know to be innocent and most people don’t care about the LW opinion on Amanda Knox.
I was reading RationalWiki about Less Wrong, to find out anything I should know about us, and they were in hilarious form about how the innocence of Amanda Knox was a compulsory belief.
So I thought “Oh, I didn’t realise we believed that.”. I’m British, and as you’d expect since the victim was British, the British press thought Amanda Knox was some sort of sexy cartwheeling antichristette. And went and read the article in question, which said: “Think about this as if it were a problem in probability.” So I did, for a couple of hours, and it was obvious that she was innocent.
So for a while I went around telling everyone that she was innocent, and they reacted how you’d expect when a middle aged man gets interested in the innocence of a pretty youngster.
And then it turned out she was, and they all think I’m a witch now.
And that is the first and only time I have seen this purported method work on something real. It works on made-up theoretical problems, Bob’s your uncle. And philosophically it’s nice.
But here we have a chance to find out something really important, or discredit something harmful. And then I’ll know. Both things.
Sometimes the answer is “You have no evidence”. (Or at least no good evidence.)
Of course, if you have no evidence that an accused criminal is guilty, you should assume they are innocent. But if you have no evidence in some medical theory, you shouldn’t be assuming the medical theory is true.
I hope I’m not assuming it. I certainly don’t believe it.
I don’t think you are wrong to have this discussion on LW. The fact that the main post got 23 upvotes also indicates that the community doesn’t think you were wrong to post this here.
I think most illnesses are based on a chain of things going wrong with the body. Various alternative treatments do sometimes produce positive results. On the other hand they often don’t consistently produce results.
I think this too. I think the chain is (mysterious Cochran-type cause)->(mysterious endocrine transport disorder)->weird polymorphous syndrome.
We don’t find out this sort of thing by expensively trying random things. Especially since the tests are terrible. We have to work it out in theory, and then make predictions where we don’t already know the answers, and then see whether they’re true. And then adjust our beliefs.
If I am sounding like a fanatic, I hope it is a Bayesian fanatic. Because that is what I am. And here I have a chance to test my beliefs on something real, and hard. And I haven’t a clue how to go about doing it.
The start is getting clearer about your own theory and what you actually believe.
If you claim to be a Bayesian fanatic, then actually reason in probabilities. Bring numbers. Be clear about how probably you consider various thesis that you made.
Then it’s worth noting that you being right means that a company might make a billion dollars of that knowledge. Especially if the solution is a special mix of hormones that could be patented to make a synthetic analog of the pig thyroid. That means that if you can convince the right person that there a 5% chance that you are right they might fund a 100,000$ trial to find out.
Just be to clear, I’m not a person who’s defending the status quo of the way the medical system works. In the last month I sat down with a person who had a cat allergy and did an NLP intervention to treat it. The next day he spent 30 minutes with a cat to test and didn’t have any allergy symptoms. I put down 2:1 chances of success beforehand in our shared prediction database.
Next month I’m at a workshops with 3-4 QS people a 3-4 academic scientists to talk about what
Let’s say it’s: “A person shy’s away from conflicts that arise when they speak up. As a result the fascia around the throat is tense. The tense fascia then presses on the thyroid. The thyroid doesn’t work properly because there’s pressure on it. Badly regulated hormones then do a mess elsewhere in the body.”
In my understanding the recent history of hormone supplementation generally isn’t good, because the body stops to produce less of the hormone if it’s supplemented.
However let’s spend more time investigating it here. Alexandra Carmichael who used to be one of the people at the head of the Quantified Self mothership build CureTogether as a database where people can report their results with different treatments.
It has 137 treatments for Fibromyalgia. The most sensible treatments seem to be getting more sleep, resting and and hot bathes. But there are also drugs listed. The first place is Low-Dose Naltrexone (LDN). Provided one doesn’t count the painkiller mariuanah, the second place as far as drug go goes to Thyroid hormone. In total it’s the 16 place in the list counting all other approaches.
That site’s a wonderful idea! And it looks as though LDN has some effect on the immune system.
So if we can trust it, it looks like the two things that attack the problem rather than the symptoms are LDN (suppresses immune reaction) and T3 (overwhelms my hypothesised immune-caused endocrine resistance).
This is the problem I keep having. Every time I see something new, it supports me. Can anyone find something that I can’t explain?
And just for the avoidance of doubt, I think taking pure T3 is a terrible idea. But John Lowe thought it worked for him and for many of his patients, and I trust John Lowe much more than I trust myself.
Science isn’t about explaining but about making successful predictions. Smart people can explain anything.
You’re conflating two different meanings of “explain”:
Construct a plausible narrative
Describe the underlying mechanism
I don’t think I’m conflating something in the context of this discussion. I think johnlawrenceaspden does focus on providing a plausible narrative instead of making falsifiable statements.
Is fair, but surely those predictions can be about bits of the medical literature that I haven’t seen yet, or haven’t understood properly, otherwise history would not be a rational endeavour.
You admitted it yourself. You’re using dodgy inferences!
This is especially bad if you have a chain of them, as the errors accumulate—if your reasoning depends on five dodgy inferences each with a 60% chance of being correct, you’re already down to 8%.
Right! So now I have an 8% chance of being right about something really serious. And so I need to make a prediction and work out whether it’s true, and then adjust. You try it!
What kind of prediction could you possibly make about “almost all the remaining unexplained human ailments”, that could be checked to see if it’s true?
And even if there was something, you haven’t actually made or tested the prediction yet. So not only have you used dodgy inferences, you’re putting the burden of proof on the wrong side. It’s not up to other people to prove it false, it’s up to you to prove it true, and if you haven’t done that yet, you have no business believing it.
http://lesswrong.com/lw/nbm/thyroid_hormones_chronic_fatigue_and_fibromyalgia/
Certainly not putting the burden of proof on the other side. Don’t believe it myself.
(a) Actually, my wonderful GP confirms that whatever phrasing he uses, the local lab won’t test FT4 unless TSH is abnormal. He’s going to try ‘FT4 IRRESPECTIVE of TSH result’ and see what happens. Of course, this is England, and you may have a different experience. The T4 tests are badly standardized, apparently you can get high FT4 by one method and low FT4 by another from the same blood sample. I don’t think they’ve ever been used for anything serious since TSH is a better test anyway, so the lab may not be acting insanely here.