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Friday, December 18, 2020

Liveblogging the FDA hearing on the Moderna Covid 19 vaccine

So Far the efficacy data has been presented. As reported in the press earlier, the vaccine is roughly 95% effective, that is roughly 95% of people who got Covid 19 during the trial were participants who received the placebo.

Importantly, the null hypothesis that just one dose is just as good as two was not rejected. The test of this null had extremely low power as almost all participants received both doses, so basically this means cases less than 4 weeks after the first dose. However, note the extreme rigidity of the FDA.

Before allowing vaccination, the FDA required proof of efficacy. Before allowing a modification from two doses 4 weeks apart to one dose, the FDA requires … I don’t know maybe if Jesus Christ returned and petitioned them for some flexibility, they would give Him a hearing, but I guess they would tell him he needed to propose (and fund) a new Phase III trial.

It is also true that there is no evidence of benefit from the second dose of Pfizer’s vaccine. It is clear that people who have received one dose of either vaccine are among those least at risk of Covid 19.

The vaccines are in very short supply. People are anxiously waiting for vaccination. Because the protocol had two doses, half of the vaccine will be reserved for the people who will benefit least.

Here there is a difference between careful science and optimal policy. In science it is crucial to write the protocol first then follow it mechanically. This is necessary so that the experimental interventions are exogenous and one can be sure they cause the observed outcomes and are not caused by observations.

However, it is not optimal policy to reduce the possible decisions to two, a priori with extremely limited data. This is what the FDA does. I think they should approve a single dose. Their rule is always to only act on extremely firm knowledge. It is, in this case, not going to be first do no harm. The second dose has side effects (mild but not zero). There is, I think, no evidence of benefits. (Again, the test has extremely low power (and I’m not sure protocol did not say the question would be addressed — if it didn’t then there is a problem — the rule decide what to do in advance applies to data analysis too — it is vital that the data not be dredged looking for a significant coefficient)). I think the point estimate is pretty much exactly zero benefit.

I think that people should be given a single dose. After everyone who wants one dose has been vaccinated, then it makes sense to give people a second dose. There is no reason to think spacing 4 weeks apart is optimal — the spacing was decided in advance.

Next speaker discussed safety. There is 0 evidence that vaccination increases the risk of anaphalactic shock. There were two cases one person who suffered anaphalaxis received placebo and one received the vaccine. The most common side effect was pain. There were no cases of severe side effects. People with a history of anaphalaxis were *not* excluded from the study.

Now a third speaker argues for unblinding the study and giving the vaccine to participants who were given the placebo. They can drop out and just get the vaccine when it is their turn. Losing the control group is not ideal but attrition will make it useless soon anyway (people will not settle for 50% chance they were vaccinated when the vaccine is approved — probably tomorrow). I agree, they have enough data and it is not ethical to leave people unvaccinated just as a control group.

Now they open for discussion with a few members of the public allowed to ask questions (the law requires this). I muted. Now they have taken a pause.

My question is why not give people just one dose until everyone who wants it has been vaccinated once ? I see no basis at all for allocating the scarce vaccine to a second dose. The scientific method does not say that optimal policy requires sticking to a protocol written before data were collected. The first do no harm principle (which I absolutely oppose in general) would imply giving one dose until there is evidence of benefit of a second dose.

Consider the case of tests for Covid 19. The test kits sent out by the CDC contained powder in tubes. One tube was the positive control — it was supposed to containt DNA with sequences corresponding to the Sars Cov2 RNA genome sequences. The tubes which were supposed to contain one of 3 oligonucleotides to be used. was contaminated with traces of that DNA. The result was that the kit as shipped reported that distilled water was infected with Sars Cov2. The hospital labs which got the kits almost immediated figured out that they could test with valid results if they didn’t use the material in the contaminated tubes, and just used 2 oligonucleotides. They could determine who had Covid 19 using the kit. But that was a modified protocol which was not FDA approved, so the FDA did not allow them to do this. The FDA also did not approve dozens of tests which were developed by the private sector.

Here the FDAs decision that they would rather be safe than sorry kept the US blind to Covid for … I think maybe a couple of weeks. Don’t look, because you haven’t proven that your glasses have exactly the right prescription is not good advice to someone on a highway. This was a very bad problem. I think the lesson learned is not that even the CDC lab sometimes makes mistakes. It was that rigidity and refusing permission is not the way to safetly.

Since then, I have been very favorably impressed by the FDAs efforts. But today I want more — I mean less — I mean approving less and allowing more flexibility. I see no case for insisting on giving people second doses with almost exactly zero evidence of efficacy. I see no case for reserving vaccine for the people who are least at risk of Covid 19. Yet I see no chance that a single dosage will be allowed.

Usual rant

In previous posts, I object to the confusion of the pure food and drug act with the scientific method. I note that it is simply a mistake to assert that the null hypothesis is to be treated as true until it is rejected by the data. The law says drugs are assumed ineffective until they are proved effective. That is US law not the scientific method. In general the decision of which of 2 hypotheses to treat as the null is arbitrary and should have no implications. I am not a scientist, but I am familiar with the Neyman Pearson framework and I consider my claims about the meaning of “null hypothesis” to be as solid as my assessment of 2+2. Both are simple math

Friday, October 02, 2020

Constitutional Nit Picking

I object to this sentence in this article by Paul Kane in the Washington Post "In such a scenario, deciding the presidency falls to the House of Representatives, but in a rare twist mandated by the 12th Amendment after the contested 1800 election, each state’s delegation counts as one vote. "

In fact, we can blame the delegates at the Constitutional Convention (as well as the 7th Congress) for that particular offence against Democracy. Back in 1800, The Constitution Article II Section 1 included "But in chusing the President, the Votes shall be taken by States, the Representation from each State having one Vote;"

The one state one vote rule does appear in the 12th Amendment, but it was already in the original Constitution.

A more important point is that this is only relevant if there is a 269-269 tie in the electoral college. The 12th amendment also says " The person having the greatest number of votes for President, shall be the President, if such number be a majority of the whole number of Electors appointed;" Notice "Electors appointed" not "More than the number of states plus half the number of representatives" or currently more than 269.

It is (still in spite of everything) inconceivable that the race be called before it was agreed who won the tipping point state, but if it is decided that a President elect must be declared while the winner of some state is contested, the matter will not go to the House voting one state one vote (as always results must be certified by the House voting the normal way one representative one vote).

It has not always been true that all states are represented in the electoral college. It hasn't always been true in my lifetime (I was born on November 9 1960 the day after electors were elected November 8 1960 but before those electors Kennedy). In 1960 the electors for Hawaii were never assigned because the outcome was contested when the electors voted. This means that Hawaii had to wait until 1964 to be represented in the electoral college after becoming a state on August 21, 1959.

Tuesday, May 26, 2020

Hobbes and Hegel

I've decided not to write a blog post on a topic about which I know little, and rather to write on a topic about which I know nothing. Consider this part of the dialectic of trolling.

Hence the question, what do Hobbes and Hegel have in common ? I admit I know a bit about Hobbes having read the first two books of Leviathan (and I bet Hobbes's mom was too bored to read the third and fourth). About Hegel I know almost exactly nothing (and more than I would like).

They are two seminal influential writers. The vibrant discussion and debate about the social contract began with Hegel largely transmitted through Locke's attempt to refute Hobbes in his second treatise on government (I have read it but not his first treatise on government).

In each case, most people addicted to the big H's do not share their conclusions or general orientation. Some phrases and words live on (social contract, dialectic, historical age) while the orginal main point is utterly rejected.

The interesting thing is that these two genuinely revolutionary writers were reactionary. Both advocated absolute monarchy. Hobbes explicitly rejected not only the British revolution, but also the ancien regime with power divided between the King and Parliament. He regretted the defeats at Naseby and Runnymeade, he contested both Cromwell and Polybius. He slashed at the division of power as sharply as Ockham.

Hegel was not so clear (the military situation has developed not necessarily to Japan's advantage). He claimed to believe that Prussia should have a constitution, and that Prussia had a constitution.

I just had an idea. I think the extroirdinarily original thoughts are the result of attempting to defend the indefensible. There were a few obsolete arguments for absolute monarchy. The first was might makes right, which was challenged by facts on the ground. The second was the divine right of kings which was hampered by the contrast between God's stubborn silence and theologians' verbosity. Something new was needed and first the social contract then the dialectic were new. I think the radicalism of Hobbes was made necessary by his extremely reactionary factionalism. I think the extreme abstraction and vagueness of Hegel [should be discussed only by people who have actually read Hegel] was a new obscurantism needed because people had ceased to look to scripture for guidance on public policy (people starting with Hobbes).

Necessity is the mother of invention, and the painful and humiliating need to find some way to defend the pretenses of a royal patron was the mother of genius.

Sunday, April 12, 2020

Experts and Me

This is much too self indulgent for www.angrybearblog.com. I am trying to understand what I think of the recent discussion of leaving things up to the experts. Donald Trump is making a very convincing case for leaving things up to experts by pretending to be able to outguess them using his gut. I remain not totally convinced.

I am definitely not willing to leave health care decisions to doctors. I am not talking about my own as I am generally healthy enough. I do insist on giving advice when is often to challenge doctors and argue with them about therapy. I am going to consider a typically good column by Michael Gerson here

The dangerous conservative case against expertise. He has a point. In particular, conservatives are often wrong when they disagree with experts (also when they are experts). Gerson happens to be my favorite conservative. I don't know how long he will remain a self identified conservative. I think he will follow his fellow Washington Post conservative quota hires Jennifer Rubin and Max Boot to neoliberalism.

He writes well enough that it is hard to quote.

I note here that he doesn't have an argument against medicare for all *or* for the claim that Covid 19 shows why it would be good

a human tendency to interpret disasters as confirmation of our existing beliefs. So the coronavirus outbreak proves the need for a border wall. [skip]”

Not every argument is strained or spurious. The pandemic has given our health-care system an X-ray, revealing disturbing racial inequities that need to be understood and addressed. But on the whole, we are right to be wary of people who claim great tragedies as the confirmation of pet theories and previous prophesies.

He just moves on, because his job is to be a conservative critiquing conservatives. I think there is also the point that it won't be enacted and so it isn't on the agenda. In particular he critiques

conservatives who look at the coronavirus outbreak and see, of all things, the discrediting of experts and expertise. In this view, the failures of the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have brought the whole profession into disrepute. The judgments of health professionals have often been no better than the folk wisdom of the Internet. The pandemic is not only further proof of the fallibility of insiders; it has revealed the inherent inaccessibility of medical truth. All of us, scientists and nonscientists, are walking blindly on the same misty moor and may stumble on medical insights.

I think he is describing a real phenomenon and he is right to denounce it. But I have some criticisms.

First, and importantly, the internet is a medium. One can't discuss the effect of relying on the internet any more than of relying on the spoken word or books. He has something in mind, but he doesn't quite define it. I think he is thinking of social media of FacebookandTwitter. I get my opinions about Covid 19 and treatments from the internet, and, in particular from

https://www.worldometers.info/coronavirus/

https://www.ncbi.nlm.nih.gov/pubmed/

and

https://clinicaltrials.gov/

Also I have read a lot about how the Wikipedia is unreliable, but know of only one gross error (the article on Ricardian equivalence).

I don't think it is possible to understand the problem without addresses the particular problem of the conservabubble. Think of edited media (the MSM). The reliability of edited news media sources varies widely. Don't trust Fox News. Don't trust the National Enquirer. Don't trust The Wall Street Journal opinion pages. Don't pretend that this is a general or symmetric problem.

My other thought is: What about the FDA ? It is, like WHO and the CDC a center of recognized expertise. It is also (unlike WHO) a center of power -- the FDA has legal authority. It has made terrible mistakes so far, and they have killed people.

In particular it is essentially 100% responsible for the delay of testing for Covid 19 in the USA. The CDC sent out test kits which had a (still not understood) problem. This would have caused at most a week of delay without the help of the FDA.

The problem appears to be with one reagent which should consist of a pair of oligonucleotides and which sometimes seems to be contaminated. I don't claim to understand what is wrong with it, but do note that it can be just left out, that the CDC test kits work fine if it is not used, and that this is one of the main ways tests are now conducted in the USA. Also all this was discovered about 1 week after the kits were mailed which was roughly 3 weeks after the Sars Cov2 sequence was published.

The further delay (roughly 2 weeks) occurred because the FDA did not authorize the use of the modified toss out the problem causing reagent test. It also placed a heavy burden for approval of tests by private agents -- hospitals, universities, and commercial testing firms.

That was the (more) fatal problem (in thousands of deaths caused).

I think there are two lessons. First there is a bias towards small c conservatism. A delay in adopting something new is always considered acceptable. This makes no sense. Another is that the expertise can be familiarity with the way things have been done (combined with the conservativism). Experts on Covid 19 testing include experts on RT-PCR and experts on obscure FDA regulations which implied that the declaration of an emergency slowed the response to the virus. The second group of experts (call them lawyers) know about current laws, rules and regulations. They don't know if they are optimal.

Notice that I haven't gotten close to saying that "medical truth" is inaccessible. One doesn't get there from questioning experts and especially not from questioning experts when they disagree.

OK I quote "And the CDC did badly mishandle the early stage of diagnostic testing." But what about the FDA ? Yes they made some mistake at the CDC, but it caused only a third of the total delay. Such problems are inevitable -- human perfection is impossible. But refusing to allow the correct solution to be used is not inevitable. By "solution" I mean solution with a solvent and solutes not including the powder which was supposed to be a pair of oligonucleotides (and may have been -- we don't know if it was contaminated).

another quote

Judgments based on that information are not infallible. But they are always preferable to the aggregate opinion of the Internet.

I am quite sure there is no such thing as the aggregate opinion on the internet. Again, he is thinking of something other than the medium. Again he ignores the fact that the peer reviewed literature is available on the internet (at least abstracts). I think he is on to somethng but the entity he has in mind is not "the internet". I'd call it "the conservabubble".

Gerson also leaves out experts. He notes the experts who warned of the pandemic and who advocated social distancing. He is right. He is also right that conservatives mostly dismissed them and that Trump is a disaster. In fact, I guess I agree with him about almost everything except his definition of "experts" and "the internet".

One aspect of the scientific literature is that extreme caution is favored. Guesses are not published (unless the person guessing is really famous). Claims to have found the answer are deliberately understated (which doesn't mean they aren't often wrong -- there is a constant struggle between the professional norms and the inclinations of enthusiasts).

But this is not appropriate as a guide for action in a crisis. The default response that we don't know and we have to do more research does not suggest what to do during that research.

The actual practice is to stick to business as usual. In medicine it is to stick to standard of care until and new therapy is proven to be superior (and the standard of proof is much stricter than the supposed proof beyond reasonable doubt which gets people locked up in prison). This makes no sense in the treatment of a disease first described 4 months ago. But it absolutely does describe actual choices made by actual doctors here "She listened patiently to Hall and expressed her concern that his suggestions did not conform to standard medical procedure or C.D.C. guidelines." The patient had Covid 19. How could there be standard medical procedure already ?

It is definitely a fact that doctors are very determined to define a standard of care (which is described in a document which in cases with which I am familiar is written by a private voluntary association of physicians). The reason for this is, I think, perfectly clear. If a patient is given care according to the standard, then bad outcomes do not imply malpractice liability. This means that sticking to the standard is sensible for the cautious physician who cares a lot about not being sued for malpractice and considers that more important than ding what, according to a posterior probability distribution updated with the available data, maximizes expected patient welfare.

This is the way it is done. The key experts include lawyers who explain malpractice liability (correctly).Then there are the standards of care, the official guidelines, whose key roles include defence in malpractice suits.

I assert that there is a problem here -- a moral problem and a policy problem.

I have been asserting this for years. As Gerson might predict, I now assert that the Covid 19 epidemic proves I was right.

Friday, March 27, 2020

Giving Boot the Boot

Your statement including the words “just Concluded” is false. You should correct the error. No one who understands hypothesis testing could have “concluded” that the null is true because it is not rejected. This is especially true if the test has low power. It is especially especially true if the test has no power at all, power exactly zero, not the tiniest but of power.

The test you cite had zero power. Not as high as one in a trillion, but 0, nada, zip, niente.

The authors did Not conclude what you claim they concluded. The paper is in Chinese but has an English abstract which you should have read before making (incorrect) claims including the word “concluded”.

In fact the authors concluded that the prognosis of Covid 19 (with conventionsl therapy) is good and that studies with larger sample sizes are needed. I am not quoting, but I am paraphrasing with some care and not with total ignorance as you did.

Also I am not shocked thst the self declared pro life party is not pro life. They don’t care. That’s why many of them are blood thirsty hawks (I am not saying all hawks are blood thirsty and trust that you have good intentions but don’t you remember “more rubble less trouble J Podhoretz, and “Bomb bomb bomb, Bomb bomb Iran” J McCain ?

where were you hiding ? (OK I know the conservabubble is airtight)