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Comment author: NatashaRostova 03 December 2016 12:26:04AM 1 point [-]

Check out Yvain's sequence on Game Theory. I've actually studied game theory at a grad level, and had nothing to learn from what he wrote. But he opened it up in a fun/interesting/well-written way, which was specifically written for this audience, and addressed relevant interests here more than a textbook.

It's challenging to imagine a sequence on introductory chemistry that would have the same appeal. Having said that, I'm sure a sufficiently educated/talented writer could do one on intro chem.

Comment author: johnlawrenceaspden 20 April 2017 09:20:18PM 1 point [-]

"Asimov on Chemistry" was a childhood favourite of mine.

Comment author: FriendlyBuffalo 20 May 2016 07:02:36AM 2 points [-]

The TSH test is actually very accurate. Third generation TSH assays are able to detect 0.02 mIU/L or less.

The problem is the way TSH testing levels are used without regard for the actual thyroid hormone levels. The relationship between TSH, T4, and T3 is much more complicated than it seems.

A good explanation of the latest research into it is here: https://www.researchgate.net/publication/263321383. The title of the paper is "Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment."

Comment author: johnlawrenceaspden 20 May 2016 10:37:11PM *  1 point [-]

Hi FriendlyBuffalo, welcome to Less Wrong!

I've got no problem with the TSH test as a test for TSH. It's really good for that, and I seriously admire its cleverness and accuracy.

In fact it probably is a good test for primary gland failure. I can't see how the gland itself could go seriously wrong without driving TSH into the stratosphere.

What I hate is the idea that TSH normal <=> 'Thyroid Symptoms, improve when treated with thyroid hormones'. I think there are other dysfunctions going on. The very idea of assessing the state of a system that complicated by measuring one variable (or even three) is ridiculous.

I'm pretty much 'clear clinical picture => therapeutic trial, and sod the blood tests' at the moment, as I think Gordon Skinner was. Of course the problem with that is you end up endorsing leeches and aromatherapy that way. I do have a lot of sympathy for basal metabolic rate, and for waking temperature as a proxy for that.

I think we both agree that some CFS/FMS is just thyroid dysfunction, and will improve with various combinations of thyroid hormones.

The only remaining question for me now is 'Is all of CFS/FMS thyroid related, or just a significant portion of it'?

Lowe reckoned that it was 1/4 primary that had been missed, 1/2 central that there's no test for, and 1/4 the mysterious resistance that he had to overwhelm with high doses of TSH. I see no reason currently to doubt his word, and I'm pretty sure that his work has saved my life (I wouldn't have put up with CFS for much longer. It was awful, and there's no way I'd have found out it was thyroid without Lowe.) So I want to dig into his ideas until I can convince myself that they're either true or false.

If they're false that's really strange. There are now two different diseases, which came into being in the 1970s, which look exactly the same as hypothyroidism, only one of them is, and one of them isn't. I have real trouble with that on Occam's razor grounds.

And that's assuming FMS/CFS/MDD are the same thing. If not then there are three new diseases and some misdiagnosed/mistreated thyroid stuff all pretending to be each other.

I'm really really busy at the moment. I'm so sorry. I've been looking for someone who knows more about this than me for months, and now you show up willing to talk and I've got urgent other things to do. But let us resume discussion at a later date. I've written quite a lot about it here as the idea developed, feel free to debunk it all in absentia mea. I'll come back to all this soon, I'm absolutely sure. I'm obsessed.

I've printed off that paper, it looks really interesting. I'm going to try very very hard not to read it instead of doing the thing I'm supposed to be doing. Thank you very much, and hope to resume discussion soon.

Comment author: RyanCarey 20 May 2016 02:51:02PM 1 point [-]

Aren't you just taking thyroid hormones analogues (not T3/T4) that are - as expected - suppressing the pituitary production of TSH?

Comment author: johnlawrenceaspden 20 May 2016 10:13:01PM *  0 points [-]

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.

Comment author: RyanCarey 17 February 2016 12:27:45AM 1 point [-]

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.

Comment author: johnlawrenceaspden 19 May 2016 09:47:35PM 0 points [-]

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.

Comment author: Alia1d 09 May 2016 06:29:04AM 2 points [-]

I’ve found the Welcome thread!

Hi, I’m Alia and I live with my husband in San Jose, California. I found this site via SlateStarCodex and having read Rationality:From AI to Zombies I think this is a fascinating and useful set of concepts and that using this type of reasoning more often is something to aspire to. I want to do more Bayesian calculations so I get more of a feel for them.

I’m also a fundamentalist* Christian. I’m perfectly ready to discuss and defend these beliefs, but I wouldn’t always bring up these beliefs in threads. I’m not trying to deceive or trick anyone, I just don’t want to derail a thread that is actually about something else. I do think it’s possible to be both a rationalist and a Christian as to stay reasonably intellectually consistent.

*(a note on why I choose the identification fundamentalist. Not long after American Christians split into mainline and fundamentalist groups, the fundamentalists got a bunch of bad press focused on certain sub-groups that were anti-intellectual. The other fundamentalists dealt with this by splitting off and re-branding themselves as evangelical. I’m not anti-intellectual and generally in the group that would self identify as evangelical, but I’m choosing to stick with the fundamentalist label for three reasons. 1) I don’t think changing the label or re-branding is a good way to deal with negative affect attached to a word. At best it just avoids the issue rather than solving the problem. 2) I don’t believe in disavowing people because they are unpopular with third parties. While I dis-agree with the anti-intellectuals on some things, the agreement on common core beliefs that lead to the fundamentalist label in the beginning is still there. 3) I think the fundamentalist label provides more clarity. The evangelicals worked hard and successfully to avoid getting over identified with and sub-group or coincidental characteristic. But as a result the label evangelical stayed vague, Individuals and groups that are more in the mainline tradition sometimes call themselves or get called evangelical. On the other hand opponents who wanted to hang on to the negative affect kept calling anything from the original fundamentalist tradition ‘fundamentalist.’ So on the I think fundamentalist will convey the most accurate idea of where I’m coming from theologically.)

Comment author: johnlawrenceaspden 09 May 2016 01:22:48PM 0 points [-]

Welcome Alia! You sure sound like one of us. Hope you like it here.

Comment author: CasioTheSane 29 April 2016 02:07:31AM *  1 point [-]

You wouldn't need to invoke the idea of 'hormone resistance' because TSH and T4 tests normally used to diagnose hypothyroidism don't measure the active hormone - T3. T4 is just a prohormone with very little direct activity on metabolic rate.

In primates, metabolism is regulated primarily in the liver by T4->T3 conversion, so if this is inhibited for any reason it will suppress metabolism without showing up on those tests. Low calorie intake, and poor nutrition are known to cause this (e.g. Euthyroid sick syndrome). In cases of poor liver conversion, supplementing T4 can actually make symptoms worse, as it will further suppress metabolism by lowering the small amount of T3 production from the thyroid (via the TSH feedback loop).

I assume you have heard of Ray Peat? I personally had good luck applying his ideas to increase my energy levels, and my pulse, body temperature, and cold tolerance raised as well - without supplementing thyroid. His general idea is pretty simple- just look at what conditions and nutrients maximize T4->T3 conversion, and provide them (low stress, high nutrient diet).

Broda Barnes work is very interesting. It blows my mind that he published a paper in The Lancet showing that desiccated thyroid lowered cholesterol levels and seemed to prevent cardiovascular disease in his patients, and that it remains virtually un-discussed and uncited (http://www.ncbi.nlm.nih.gov/pubmed/13796871).

Comment author: johnlawrenceaspden 08 May 2016 11:23:29PM *  1 point [-]

Hi, there can be all sorts of things going wrong! Mysterious resistances, gland failures, conversion disorders, broken pituitary, broken hypothalamus, faulty deiodinase enzymes, etc. All potentially inherited or acquired. We really do seem to have no idea how this complicated system works or what it's all for, or what can cause it to go wrong.

But I would have thought that if there was widespread 'central hypothyroidism', someone would have twigged by now, since that form does show up if you do a full panel of hormone tests.

Or I would have thought that when I wrote this. By now I am in such despair about the pitiful state of medical research that I wouldn't be surprised if they'd never thought to look, so maybe it is all just perfectly obvious from blood tests and the fools have ignored it.

And the question of 'what is the optimal treatment' is bound to be tricky. I'm just trying to demonstrate that the problems exist and are widespread and thus worth looking at!

Although Skinner certainly thought 'clinical hypothyroidism' could usually be fixed by bunging enough T4 at the problem. He does mention in his book that he sometimes used T3 or NDT, but he doesn't go into details. Various other people say 'mostly T4 with a bit of extra T3', but no-one has particularly clear ideas on what works and what doesn't or why.

Thanks for the reference to Ray Peat, I hadn't heard of him before. Can you link to the best expression of his thoughts?

Comment author: gjm 06 May 2016 10:56:50AM -1 points [-]

honestly curious how obvious it is

To me: about three seconds' thought after reading your statement. But I'm an actual mathematician and therefore not necessarily typical.

Comment author: johnlawrenceaspden 06 May 2016 11:33:32AM 2 points [-]

Took me about 30 seconds, but I'm only an ex-mathematician and I'm not as clever as g!

Comment author: NancyLebovitz 23 April 2016 07:07:05PM 0 points [-]

http://www.ncbi.nlm.nih.gov/pubmed/9513740

What do you make of this? I'll note that it's a very small sample size, and I don't think it says whether those particular CFS patients report feeling chilled all the time. It also wouldn't surprise the hell out of me if there's some way a body can go wrong so that a person has a normal core temperature (what about the periphery?), but feels chilled anyway.

Also, in regards to being stupid-- I know some people with CFS who seem pretty smart, but who complain of brainfog. Perhaps they do most or all of their posting when the brainfog lifts.

Comment author: johnlawrenceaspden 23 April 2016 11:59:39PM *  0 points [-]

Hi Nancy, thanks! I've already seen that, it's in the evidence section of:

http://lesswrong.com/r/discussion/lw/nef/the_thyroid_madness_core_argument_evidence/

Even more disconfirmy is: http://www.sciencedirect.com/science/article/pii/S0024320515301223

Where some Turkish fibromyalgia patients are actually hotter than they should be, to the point where the authors suggest it as a diagnostic criterion!

There's no doubt they're evidence against. I would have predicted the opposite. When I first saw these two papers (within half an hour) I gave up on the idea. I even told my GP I'd managed to refute it.

But after a couple of days of not believing it, I was just terribly confused, and I realised that they leave me wiggle room.

Basal metabolic rate has to be strongly related to surface temperature (all other things being constant), but there's no reason it should be related to core temperature.

And the thyroid hormones control the basal (i.e. sleeping) metabolic rate, not the active (field) rate.

So I can ignore the Turks (hot during the day), and the main thrust of the Hamilos paper, even though I feel really weaselly doing it.

But, the Hamilos group explicitly considered surface temperature, and they say that they measured basal metabolic rate and it was normal, but they don't give any details, and I can't figure out what they did with either.

If they were careless with the metabolic rate (say, measured it after a rest during the day), it's meaningless as a hypothyroid test. In fact during the day the metabolic rate might actually be higher, if metabolism in hypothyroidism is inefficient because the mitochondria aren't working properly.

And their core graphs do look a bit funny for CFS (but not for depression, which looks normal, sigh..)

On the other hand, Lowe checked for basal metabolic rate and temperature in Fibromyalgia, and found them both way low. I doubt he'd actually have gone to the trouble of trying to break his own idea formally and then faked his data, but it's possible.

And on the third hand, the whole reason for the Hamilos paper is that their CFS patients have been complaining about both low and high temperatures. Why are they doing that? I don't think the 'occult hypothyroidism' idea is well known in CFS circles. One hypothyroid symptom was the rather paradoxical 'intolerance to heat/intolerance to cold'.

I'm just hopelessly confused.

These papers alone, strong evidence against, I think, but not quite refutation.

All the other evidence I've ever seen, strongly in favour.

Skinner's open trial pretty much alone has convinced me that just thyroxine should work, which I didn't believe earlier because it's far too obvious to have been missed. And he also treated depression with it. He considered the possibility of placebo effect, and called for formal trial as one should, but thought it unlikely because the improvements were huge, some of them not subjective, and they were very lasting. And he was a medical researcher, so he knew about fooling himself. And his results are just far too good to be a mistake. He has to be 'right or lying'.

And actually, it seems medical statisticians don't believe in 'the placebo effect'. It's mostly regression to the mean and people trying not to disappoint doctors by saying that things don't work. (That's a bad bias if ever I saw one!)

But people who've been ill for years don't suddenly make full recoveries because you've given them something that should make them more ill, especially when they've all tried loads of freaky stuff before.

The Pollock thing is inexplicable unless their 100mg fixed thyroxine dose helped at least some of their patients. And whatever I think of their selection criteria, they did control properly, and neither of their groups could tell the placebo pills from the thyroxine explicitly, even though the controls were clearly made a bit ill by thyroxine.

In short, I don't actually believe the (widespread occult hypothyroidism) idea. But I do think it's plausible, and I think there's something funny going on with thyroids and all these 'new diseases' and I think I've made a good enough argument that it should be properly trialed.

So I'm now risking talking about it on the reddit CFS group. It seems to be news to them. I'm a bit worried they're all going to do what I did, but they are adults, and it's not very dangerous. I gave them Billewicz statistical test, which is designed to tell 'things that look like hypothyroidism' from 'actual hypothyroidism' by looking at the subtle symptoms like ankle reflexes, and slow movements, and hoarseness and puffy eyes.

So far two people score 'definitely hypothyroid', one 'definitely not', and one hasn't done the test but say's he's got a really good doctor treating his hypothyroidism who's titrating various mixes of thyroid hormones to get rid of all his symptoms but even when they're all gone he's still got disabling fatigue.

But that's even more nuts!

Some CFS is 'occult hypothyroidism' and some is 'something else, definitely not hypothyroidism' is completely crackpot. Not just ordinary crackpot. Occams' Razor! Two different causes for the same thing!

I think we need to take a proper look at all this.

As for the stupidity, whatever I was suffering from (that really does appear to have been occult hypothyroidism by all measures, and that's been apparently completely fixed for months by Floradix and desiccated thyroid) made me as thick as shit. I was so stupid, I couldn't even read. At one point I couldn't count to six. But I still got a couple of hours of lucidity every day, usually in the late evening.

Thanks ever so for you interest, and do send me any more things you dig up. I'm as blind as anyone else, and perfectly capable of ignoring evidence against, even though I'm trying really hard to allow for that!

Comment author: AstraSequi 23 April 2016 02:02:03PM *  0 points [-]

Sure, this experiment is evidence against 'all fat, tired people with dry hair get better with thryoxine'. No problem there.

Okay, but you said it was evidence in favor of your own hypothesis. That’s what my question was about.

Yes, it is kind of odd isn't it? One of the pills apparently made them a bit unwell, and yet they couldn't tell which one. I notice that I am confused.

Suppose they’re measuring on a 10-point scale, and we get ordered pairs of scores for time A and time B. One person might have 7 and 6, another has (4,3), another has (5,6), then (9,7), (7,7), (4,5), (3,2)...Even if they’re aware of their measurements (which they might not be), all sorts of things affect their scores and it’s unlikely that any one person would be able to make a conclusion. You’re basically asking an untrained patient to draw a conclusion from an n of 1.

But that's awful! Once, there was a diagnostic method, and a treatment that worked fine, that everyone thought was brilliant. Then they invented a test, which is very clever, and a good test for what it tests, and the result of that is that lots of people are ill and don't get the treatment any more and have to suffer horribly and die early.

There are several assumptions here that I think are probably incorrect, the biggest being the causal link between introducing the test and people suffering. But what I described before is just the application of reductionism to better distinguish between disease states based on their causal mechanism.

If that's normal then there's something badly wrong with normal. A new way of measuring things should help!

Sometimes, but replacing an objective measurement with a subjective one isn’t usually a step forward.

Seriously, if 'start off with low doses and keep raising the dose until you get a response' is inaccessible to testing, then something is broken.

Problems with this include: you can’t justify the parameters of the dose increase, you still have to agree on how to measure the response, and you also have a multiple testing issue. It isn’t inaccessible, but it’s a complication (potentially a major one), and that’s just in the abstract. Practically, in any one situation there might be another half dozen issues that wouldn’t be apparent to anyone who isn’t an expert.

But in fact, just 'low basal metabolic rate in CFS' would be good evidence in favour, I think. We can work out optimal treatments later.

Not knowing anything about the subject, I would expect to observe a low basal metabolic rate in CFS regardless of its ultimate cause or causes.

At that point, we're all post-modernists aren't we? The truth is socially determined.

No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.

Science is not unreliable...

You’re talking about the overall process and how science moves in the direction of truth, which I agree with. I’m talking on the level of individual papers and how our current best knowledge may still be overturned in the future. But you can leave out “just like..wisdom” from the paragraph without losing the main points.

There's at least a possibility here that medical science is getting beaten hollow by chiropractors and quack doctors and internet loonies, none of whom have any resources or funding at all.

The alt med people have a lot of funding. It’s a multi-billion-dollar industry.

Even the possibility is enough to make me think that there's something appallingly badly wrong with the methods and structure of medical science.

A few things, not just one, but it’s the best we have at the moment.

Comment author: johnlawrenceaspden 23 April 2016 06:06:01PM *  1 point [-]

No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.

So, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p.

Is the only way we learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?

And nothing done outside the system is worth anything at all?

And the opinions of patients and doctors are 'placebo effect?'.

And the patients' obvious symptoms are 'psychosomatic/somatoform/hypochondriac/malingering'? All the same bloody word, changed every decade or so when people realise what they mean.

And someone invents a wonderful new measurement technique that bears on a hard problem, and it's used to make things worse?

Comment author: AstraSequi 23 April 2016 02:02:03PM *  0 points [-]

Sure, this experiment is evidence against 'all fat, tired people with dry hair get better with thryoxine'. No problem there.

Okay, but you said it was evidence in favor of your own hypothesis. That’s what my question was about.

Yes, it is kind of odd isn't it? One of the pills apparently made them a bit unwell, and yet they couldn't tell which one. I notice that I am confused.

Suppose they’re measuring on a 10-point scale, and we get ordered pairs of scores for time A and time B. One person might have 7 and 6, another has (4,3), another has (5,6), then (9,7), (7,7), (4,5), (3,2)...Even if they’re aware of their measurements (which they might not be), all sorts of things affect their scores and it’s unlikely that any one person would be able to make a conclusion. You’re basically asking an untrained patient to draw a conclusion from an n of 1.

But that's awful! Once, there was a diagnostic method, and a treatment that worked fine, that everyone thought was brilliant. Then they invented a test, which is very clever, and a good test for what it tests, and the result of that is that lots of people are ill and don't get the treatment any more and have to suffer horribly and die early.

There are several assumptions here that I think are probably incorrect, the biggest being the causal link between introducing the test and people suffering. But what I described before is just the application of reductionism to better distinguish between disease states based on their causal mechanism.

If that's normal then there's something badly wrong with normal. A new way of measuring things should help!

Sometimes, but replacing an objective measurement with a subjective one isn’t usually a step forward.

Seriously, if 'start off with low doses and keep raising the dose until you get a response' is inaccessible to testing, then something is broken.

Problems with this include: you can’t justify the parameters of the dose increase, you still have to agree on how to measure the response, and you also have a multiple testing issue. It isn’t inaccessible, but it’s a complication (potentially a major one), and that’s just in the abstract. Practically, in any one situation there might be another half dozen issues that wouldn’t be apparent to anyone who isn’t an expert.

But in fact, just 'low basal metabolic rate in CFS' would be good evidence in favour, I think. We can work out optimal treatments later.

Not knowing anything about the subject, I would expect to observe a low basal metabolic rate in CFS regardless of its ultimate cause or causes.

At that point, we're all post-modernists aren't we? The truth is socially determined.

No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.

Science is not unreliable...

You’re talking about the overall process and how science moves in the direction of truth, which I agree with. I’m talking on the level of individual papers and how our current best knowledge may still be overturned in the future. But you can leave out “just like..wisdom” from the paragraph without losing the main points.

There's at least a possibility here that medical science is getting beaten hollow by chiropractors and quack doctors and internet loonies, none of whom have any resources or funding at all.

The alt med people have a lot of funding. It’s a multi-billion-dollar industry.

Even the possibility is enough to make me think that there's something appallingly badly wrong with the methods and structure of medical science.

A few things, not just one, but it’s the best we have at the moment.

Comment author: johnlawrenceaspden 23 April 2016 06:02:37PM 1 point [-]

No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.

So, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p.

Is the only way you learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?

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