Category: Medicine

Jason Abaluck writes me about masks and the Bangladesh RCT study

This is all him, no double indent though:

“As a regular reader of your blog and one of the PIs of the Bangladesh Mask RCT (now in press at Science), I was surprised to see your claim that, “With more data transparency, it does not seem to be holding up very well”:

  1. The article you linked claims, in agreement with our study, that our intervention led to a roughly 10% reduction in symptomatic seropositivity (going from 12% to 41% of the population masked). Taking this estimate at face value, going from no one masked to everyone masked would imply a considerably larger effect. Additionally:
    1. We see a similar – but more precisely estimated – proportionate reduction in Covid symptoms [95% CI: 7-17%] (pre-registered), corresponding to ~1,500 individuals with Covid symptoms prevented
    2. We see larger proportionate drops in symptomatic seropositivity and Covid in villages where mask-use increased by more (not pre-registered), with the effect size roughly matching our main result

The naïve linear IV estimate would be a 33% reduction in Covid from universal masking. People underwhelmed by the absolute number of cases prevented need to ask, what did you expect if masks are as effective as the observational literature suggests? I see our results as on the low end of these estimates, and this is precisely what we powered the study to detect.

  1. Let’s distinguish between:
    1. The absolute reduction in raw consenting symptomatic seropositives (20 cases prevented)
    2. The absolute reduction in the proportion of consenting symptomatic seropositives (0.08 percentage points, or 105 cases prevented)
    3. The relative reduction in the proportion of consenting symptomatic seropositives (9.5% in cases)

Ben Recht advocates analyzing a) – the difference in means not controlling for population. This is not the specification we pre-registered, as it will have less power due to random fluctuations in population (and indeed, the difference in raw symptomatic seropositives overlooks the fact that the treatment population was larger – there are more people possibly ill!). Fixating on this specification in lieu of our pre-registered one (for which we powered the study) is reverse p-hacking.

RE: b) vs. c), we find a result of almost identical significance in a linear model, suggesting the same proportionate reduction if we divide the coefficient by the base rate. We believe the relative reduction in c) is more externally valid, as it is difficult to write down a structural pandemic model where masks lead to an absolute reduction in Covid regardless of the base rate (and the absolute number in b) is a function of the consent rate in our study).

  1. It is certainly true that survey response bias is a potential concern. We have repeatedly acknowledged this shortcoming of any real-world RCT evaluating masks (that respondents cannot be blinded). The direction of the bias is unclear — individuals might be more attuned to symptoms in the treatment group. We conduct many robustness checks in the paper. We have now obtained funding to replicate the entire study and collect blood spots from symptomatic and non-symptomatic individuals to partially mitigate this bias (we will still need to check for balance in blood consent rates with respect to observables, as we do in the current study).
  1. We do not say that surgical masks work better than cloth masks. What we say is that the evidence in favor of surgical masks is more robust. We find an effect on symptomatic seropositivity regardless of whether we drop or impute missing values for non-consenters, while the effect of cloth masks on symptomatic seropositivity depends on how we do this imputation. We find robust effects on symptoms for both types of masks.

I agree with you that our study identifies only the medium-term impact of our intervention, and there are critically important policy questions about the long-term equilibrium impact of masking, as well as how the costs and benefits scale for people of different ages and vaccination statuses.”

An update on the mask debate

I am long since tired of this debate, and I see that a lot of people are not joining it in the best of faith.  I can pass along a few updates, namely this study, with some critical commentary attached.  And here is more on the Bangladeshi mask RCT.  With more data transparency, it does not seem to be holding up very well.

That said, I am not sure that either calculation really matters.  Any good assessment of mask efficacy has to be radically intertemporal in nature, and I mean for the entirety of the pandemic.  “Not getting infected” now may well raise your chance of getting infected later on, and that spans for longer than any feasibly designed RCT.  And have you heard about the new “Nu” variant?  It may turn out not to matter, but it does remind us that the pandemic is not over yet.

As a simple first approximation, think of the real value of masks as “a) how many infections are delayed for how long, plus improvements in treatment in the meantime, plus b) how many infections are avoided altogether.”  Even a well-designed RCT is going to focus on a version of b), but only for a limited period of time.  The extant studies don’t at all consider “plus improvements in treatment in the meantime,” or when some of those protected by masks for say a year or two might nonetheless later catch Covid later yet.  So those RCTs, no matter what their results, are grabbing only one leg of the elephant.

To make matters more complicated yet, a “very small” efficacy for masks might (yes, might) translate into a much larger final effect, due to effective R (sometimes) being greater than 1.  So finding a very small effect for masks doesn’t mean masks are only slightly effective.  As the pandemic is ending, you might (again might) have had one less “pandemic cycle” than if you hadn’t tried masks at all.  You can think of masks as a kind of lottery ticket on “one big gain,” paying off only when the timing is such that the masks have helped you choke off another Covid wave.  Again, the RCT is not capable of estimating that probability or the magnitude of its effect.

Yet another part of my mental model of masks has evolved to be the following.  You have two sets of countries, countries that manage Covid well and countries that don’t, argue all you want who goes into which bin but that isn’t the point right now.

Now consider the countries that don’t manage Covid well.  They might wish to stretch out their epidemics over time, so that better treatments arrive, subject to economic constraints of course.  But the countries that manage Covid well probably want the poorly-managed countries to reach herd immunity sooner rather than later, if only to lower the ongoing risk of transmission from a poorly-managed country to a well-managed country.  And to lower the risk of those countries birthing new variants, just as southern Africa now seems to have birthed the Nu variant.

So we have two major points of view, represented by multiple countries, one wanting quicker resolution for the poorly managed countries but the other wanting slower resolution.  Does any study of masks take those variables into account?  No.  Nor is it easy to see how it could.

To be clear, I am not arguing masks don’t work, nor am I making any claims about how much masks may or may not protect you individually, or the people you interact with.  I am claiming that at the aggregate social level we are quite far from knowing how well masks work.

I say it is third doses we should be doubling down on, not masks.  To be clear, I am fine with wearing masks myself, I am used to it, and I dislike it but I don’t hate it.  On this issue, I am not one of those people translating his or her own snowflake-ism into some kind of biased policy view.

But the emerging science on third doses is much stronger, and most countries have been dropping the ball on that one.

Air Pollution Reduces Health and Wealth

Great piece by David Wallace-Wells on air pollution.

Here is just a partial list of the things, short of death rates, we know are affected by air pollution. GDP, with a 10 per cent increase in pollution reducing output by almost a full percentage point, according to an OECD report last year. Cognitive performance, with a study showing that cutting Chinese pollution to the standards required in the US would improve the average student’s ranking in verbal tests by 26 per cent and in maths by 13 per cent. In Los Angeles, after $700 air purifiers were installed in schools, student performance improved almost as much as it would if class sizes were reduced by a third. Heart disease is more common in polluted air, as are many types of cancer, and acute and chronic respiratory diseases like asthma, and strokes. The incidence of Alzheimer’s can triple: in Choked, Beth Gardiner cites a study which found early markers of Alzheimer’s in 40 per cent of autopsies conducted on those in high-pollution areas and in none of those outside them. Rates of other sorts of dementia increase too, as does Parkinson’s. Air pollution has also been linked to mental illness of all kinds – with a recent paper in the British Journal of Psychiatry showing that even small increases in local pollution raise the need for treatment by a third and for hospitalisation by a fifth – and to worse memory, attention and vocabulary, as well as ADHD and autism spectrum disorders. Pollution has been shown to damage the development of neurons in the brain, and proximity to a coal plant can deform a baby’s DNA in the womb. It even accelerates the degeneration of the eyesight.

A high pollution level in the year a baby is born has been shown to result in reduced earnings and labour force participation at the age of thirty. The relationship of pollution to premature births and low birth weight is so strong that the introduction of the automatic toll system E-ZPass in American cities reduced both problems in areas close to toll plazas (by 10.8 per cent and 11.8 per cent respectively), by cutting down on the exhaust expelled when cars have to queue. Extremely premature births, another study found, were 80 per cent more likely when mothers lived in areas of heavy traffic. Women breathing exhaust fumes during pregnancy gave birth to children with higher rates of paediatric leukaemia, kidney cancer, eye tumours and malignancies in the ovaries and testes. Infant death rates increased in line with pollution levels, as did heart malformations. And those breathing dirtier air in childhood exhibited significantly higher rates of self-harm in adulthood, with an increase of just five micrograms of small particulates a day associated, in 1.4 million people in Denmark, with a 42 per cent rise in violence towards oneself. Depression in teenagers quadruples; suicide becomes more common too.

Stock market returns are lower on days with higher air pollution, a study found this year. Surgical outcomes are worse. Crime goes up with increased particulate concentrations, especially violent crime: a 10 per cent reduction in pollution, researchers at Colorado State University found, could reduce the cost of crime in the US by $1.4 billion a year. When there’s more smog in the air, chess players make more mistakes, and bigger ones. Politicians speak more simplistically, and baseball umpires make more bad calls.

As MR readers will know Tyler and I have been saying air pollution is an underrated problem for some time. Here’s my video on the topic:

The Covid pandemic is not taking the very best of turns

This was emailed to me, but I am not doing a double indent…in any case I fear the person might be right…

“The prevailing sentiment is that the COVID pandemic is close to over. The vaccines are of course miraculous but we are not currently on a good trajectory.

  • It is increasingly clear that two shots plus a booster of our current vaccines are the least one needs to have effective medium-term protection. Almost nowhere (least of all the US) is on track to reach this kind of coverage. The messaging in the US remains mistaken, where the CDC to this day recommends boosters only for those aged 50 and older. More broadly, the institutional confusion around boosters shows that the adults are not yet in charge.
  • Even though Delta arose in the spring, we are still vaccinating (and boosting) people with the original Wuhan strain. This is insane, and probably meaningfully less effective, and yet nobody is up in arms about it.
  • Severe outbreaks are manifestly possible even in exceptionally vaccinated populations, especially when booster uptake is low. See: Singapore, Gibraltar, Ireland. One should assume that almost every part of the US will see significant waves before COVID “ends”, whatever that turns out to mean. Note that just 60% of the US population is vaccinated today with two doses.
  • There is early suggestive evidence from Israel that boosters may wane.
  • Waning aside, it’s clear that breakthrough infections in boosted individuals are not uncommon. While the vast majority of those infections are not severe, this does mean that there will still be plenty of mutagenesis.
  • It’s unclear that longitudinal cross-immunity is strong. Getting COVID is not enough to confer long-term protection. We probably can’t just “get this over with”, even if we are willing to tolerate a large number of one-time deaths.
  • The currently-breaking news about the South African Nu strain shows that arguments about how the spike protein is running out of mutation search space are almost certainly wrong.
  • While the fog of war is thick right now, the early data on Nu suggests that it may be a big deal. Even if it’s not, however, it has been obvious since we got the vaccines that vaccine escape is a concern. You can debate whether the probability of a vaccine escaping variant is 20% or 80%, but in any case we need effective contingency plans in place. If we fail to respond effectively to Nu, that will be a considerably greater institutional failure than anything that happened at the outset of the pandemic. We’ve had almost two years since the first COVID case and one year from the vaccine approvals to prepare. So I ask: what is the plan for the vaccine-escaping variant?

On current trends, it looks like we will probably need one of two things to effectively end the pandemic: (1) very effective COVID therapeutics (paxlovid, molnupiravir, and fluvoxamine all being candidates but my guess is that none is a silver bullet) or (2) pan-coronavirus vaccines (with broader protection than what is currently available).

It isn’t over yet.

P.S. Has any U.S. health body recommended the clinical use of fluvoxamine (an already-approved drug), or has the FDA given any guidance as to when it might approve paxlovid? If not, can they outline their reasoning? 1,600 Americans died of COVID on Nov 24.”

Nu, a variant of real concern

Here is the Eric Topol thread.  Do read it.  Here is the scary graph, based on preliminary data.  Here is Bloom Lab.  Here is a layperson’s take from the Times of London:

When was the variant first discovered?
South African authorities raised the alarm at 2pm on Tuesday of this week, when they found samples with a significant number of worrying mutations.

The samples dated from tests taken on November 14 and 16. On Wednesday, even as scientists were analysing the genome, other samples were found in Botswana and China, originating from travellers from South Africa.

Why were scientists initially concerned by this variant?
The spike protein is the tool a virus uses to enter cells, and the part of it our vaccines are trained to spot. This variant had 32 mutations in the spike — meaning it would look different to our immune system and behave differently when attacking a body. As a virologist at Imperial College put it, it was a “horrific spike profile”.

Why has worry increased over the course of the week?
When geneticists and virologists looked at the mutations they realised there was a high likelihood they could increase its transmissibility or help it evade immunity. But these concerns were still theoretical. However, today South African scientists spotted a quirk in the testing regimen. PCR tests look for three genes in the coronavirus and amplify them. If, however, the virus was this variant they were only able to amplify two.

In the province of Gauteng, where the proportion of tests coming back positive has rocketed to one in three, they found the proportion in which only two genes were amplified has also rocketed.

What does this mean?
There are three options. It is still possible — though unlikely — this is chance, with the variant’s apparently increased spread relating to an unusual cluster. If it does have a genuine advantage, then it is either better able to spread or better able to infect people who have prior immunity — either from vaccination or infection. Or, it is both.

This might come to nothing, but it is definitely a matter of concern.  One more general point is that even if Nu is a non-event, it seems to show that the space for possible significant mutations is largely than we had thought.

By any other name

The Northern Territory’s Covid-19 outbreak is expected to grow beyond locked-down areas after nine new cases were detected in the remote community of Binjari, about 320km south of Darwin.

Binjari and nearby Rockhole have been placed into strict lockdown in response to the outbreak, and the Australian defence force has been called in to help with transferring positive cases and close contacts [sic].

The NT’s chief minister, Michael Gunner, on Sunday said a 78-year-old woman was being treated in Royal Darwin hospital, while the other eight cases had been taken to the Howard Springs quarantine centre.

Here is the full story.  And from another story:

“We’ve shared our supply of vaccine with Aboriginal health organisations so they had enough consistent supply for everyone in their care to have a chance to be vaccinated over the past seven months,” Gunner said in a statement.

I wonder what they think Gibraltar should do.  Didn’t all the Australians tell me on Twitter that things would be back to normal soon, once enough vaccines were distributed?

The weirdness of government variation in Covid-19 responses

That is the new Substack post from Richard Hanania, here is one excerpt:

But imagine at the start of the pandemic, someone had said to you “Everyone will face the existence of the same disease, and have access to the exact same tools to fight it. But in some EU countries or US states, people won’t be allowed to leave their house and have to cover their faces in public. In other places, government will just leave people alone. Vast differences of this sort will exist across jurisdictions that are similar on objective metrics of how bad the pandemic is at any particular moment.”

I would’ve found this to be a very unlikely outcome! You could’ve convinced me EU states would do very little on COVID-19, or that they would do lockdowns everywhere. I would not have believed that you could have two neighboring countries that have similar numbers, but one of them forces everyone to stay home, while the other doesn’t. This is the kind of extreme variation in policy we don’t see in other areas.

It’s similar when you look at American jurisdictions.

And:

As the political reaction to COVID-19 has surprised me, I’m still trying to figure it out. But for now I can say it’s shifted my priors in a few ways.

  1. People are more conformist than I would have thought, being willing to put up with a lot more than I expected, at least in Europe and the blue parts of the US.
  2. Americans in Red States are more instinctively anti-elite than I would have thought and can be outliers on all kinds of policy issues relative to the rest of the developed world (I guess I knew that already).
  3. Partisanship is much stronger than I thought. When I saw polls on anti-vax sentiment early in the pandemic, I actually said it would disappear when people would have to make decisions about their own lives and everyone could see vaccines work. This largely didn’t happen. Liberals in Blue States masking their kids outdoors is the other side of this coin. Most “Red/Blue Team Go” behavior has little influence on people’s lives. For example, deciding to vote D or R, or watch MSNBC or Fox, really doesn’t matter for your personal well-being. Not getting vaccinated or never letting your children leave the house does, and I don’t recall many cases where partisanship has been such a strong predictor of behavior that has such radical effects on people’s lives.
  4. Government measures that once seemed extreme can become normalized very quickly.
  5. The kinds of issues that actually matter electorally are a lot more “sticky” than I would have expected. Issues like masks and lockdowns, though objectively much more important than the things people vote on, are not as politically salient as I would have thought. A mask mandate for children eight hours a day strikes me as a lot more important than inflation, but it seems not to be for electoral purposes. If an asteroid was about to destroy earth and Democrats and Republicans had different views on how to stop it, people would just unthinkingly believe whatever their own side told them and it would not change our politics at all.
  6. Democratically elected governments have a lot more freedom than I thought before, especially if elites claim that they are outsourcing decisions to “the science.” Moreover, “the science” doesn’t even have to be that convincing, and nobody will ask obvious questions like how “the science” can allow for radically different policy responses in neighboring jurisdictions without much of a difference in results. This appears true everywhere in the developed world but in Red State America, where people really hate experts, regardless of whether they’re right or wrong.

You should all be getting Richard’s Substack.  Of all the “new thinkers” on the Right, he is the one who most combines extreme smarts and first-rate work ethic, with non-conformism thrown in to boot.  Read him!

The Great Resignation: Health Care Workers

We are short a million health care workers. Today with extreme stress on the system there are 16 million health care workers, about five hundred thousand fewer than when the pandemic began in January of 2020 and about one million fewer than would be expected based on decades of growth. A loss of this many workers is unprecedented.

Ed Yong in the Atlantic discusses Why Health-Care Workers are Quitting in Droves:

Health-care workers, under any circumstances, live in the thick of death, stress, and trauma. “You go in knowing those are the things you’ll see,” Cassandra Werry, an ICU nurse currently working in Idaho, told me. “Not everyone pulls through, but at the end of the day, the point is to get people better. You strive for those wins.” COVID-19 has upset that balance, confronting even experienced people with the worst conditions they have ever faced and turning difficult jobs into unbearable ones.

In the spring of 2020, “I’d walk past an ice truck of dead bodies, and pictures on the wall of cleaning staff and nurses who’d died, into a room with more dead bodies,” Lindsay Fox, a former emergency-medicine doctor from Newark, New Jersey, told me. At the same time, Artec Durham, an ICU nurse from Flagstaff, Arizona, was watching his hospital fill with patients from the Navajo Nation. “Nearly every one of them died, and there was nothing we could do,” he said. “We ran out of body bags.”

…Many health-care workers imagined that such traumas were behind them once the vaccines arrived. But plateauing vaccination rates, premature lifts on masking, and the ascendant Delta variant undid those hopes. This summer, many hospitals clogged up again. As patients waited to be admitted into ICUs, they filled emergency rooms, and then waiting rooms and hallways. That unrealized promise of “some sort of normalcy has made the feelings of exhaustion and frustration worse,” Bettencourt told me.

Health-care workers want to help their patients, and their inability to do so properly is hollowing them out. “Especially now, with Delta, not many people get better and go home,” Werry told me. People have asked her if she would have gone to nursing school had she known the circumstances she would encounter, and for her, “it’s a resounding no,” she said. (Werry quit her job in an Arizona hospital last December and plans on leaving medicine once she pays off her student debts.)

…Many have told me that they’re bone-weary, depressed, irritable, and (unusually for them) unable to hide any of that. Nurses excel at “feeling their feelings in a supply closet or bathroom, and then putting their game face back on and jumping into the ring,” Werry said. But she and others are now constantly on the verge of tears, or prone to snapping at colleagues and patients. Some call this burnout, but Gerard Brogan, the director of nursing practice at National Nurses United, dislikes the term because “it implies a lack of character,” he told me. He prefers moral distress—the anguish of being unable to take the course of action that you know is right.

Health-care workers aren’t quitting because they can’t handle their jobs. They’re quitting because they can’t handle being unable to do their jobs.

Hat tip: Matt Yglesias.

The Paxlovid Paradox

Zvi at LessWrong rounds up the COVID news including this excellent bit on Pfizer’s anti-Covid pill Paxlovid which looks to be very effective but is not yet FDA approved.

The trial was stopped due to ‘ethical considerations’ for being too effective. You see, we live in a world in which:

  1. It is illegal to give this drug to any patients, because it hasn’t been proven safe and effective.
  2. It is illegal to continue a trial to study the drug, because it has been proven so safe and effective that it isn’t ethical to not give the drug to half the patients.
  3. Who, if they weren’t in the study, couldn’t get the drug at all, because it is illegal due to not being proven safe and effective yet. 
  4. So now no one gets added to the trial so those who would have been definitely don’t get Paxlovid, and are several times more likely to die.
  5. But our treatment of them is now ‘ethical.’
  6. For the rest of time we will now hear about how it was only seven deaths and we can’t be sure Paxlovid works or how well it works, and I expect to spend hours arguing over exactly how much it works.
  7. For the rest of time people will argue the study wasn’t big enough so we don’t know the Paxlovid is safe.
  8. Those arguments will then be used both by people arguing to not take Paxlovid, and people who want to require other interventions because of these concerns.
  9. FDA Delenda Est.

Politicizing Medicine is Dangerous

Politicizing medicine is dangerous. Tens of thousands of people are dead because vaccines became politicized and people chose political identity over rationality. Yet instead of trying to depoliticize medicine, the AMA has doubled down and is going full woke. The AMA’s Advancing Health Equity: A Guide to Language, Narrative and Concepts is so over the top I thought at first it was satire from the BabylonBee. The guide, for example, recommends that instead of talking about poor health among low-income people that physicians should blame “landowners and large corporations” for “increasingly centralizing political and financial power wielded by a few” and limiting “prospects for good health and well-being for many groups.” Put aside that this is at best tendentious and at worst utterly fallacious and just imagine that you are a landowner or work for a large corporation (that’s most of us!). Would you trust a doctor spouting this rhetoric or might you feel that such a doctor doesn’t have your best interests at heart?

Conor Friedersdorf puts it well:

The medical profession won’t remain more broadly trusted than left-wing activists if the two become indistinguishable. And that’s what will happen if doctors follow the guide’s advice. Instead of saying, “Low-income people have the highest level of coronary artery disease,” it urges health professionals to substitute this doctrinaire sentence: “People underpaid and forced into poverty as a result of banking policies, real estate developers gentrifying neighborhoods, and corporations weakening the power of labor movements, among others, have the highest level of coronary artery disease.”

In a section attacking “the narrative of individualism,” the guide posits that health promotion “typically means educating people as individuals,” and urges “shifting this narrative, from the individual to the structural, in order to more fully understand the root causes of health inequities in our society.” It’s already hard enough to get my conservative grandfather to heed his doctors about how best to care for a bad back worn down from decades in construction. A new narrative meant to problematize real-estate developers or individualism would not improve his medical condition, but it would inflame his temper. One wonders if the AMA and the AAMC grasp how many patients of all races and socioeconomic groups (never mind doctors) strongly disagree with the agenda that the two organizations are pushing. Either way, patients will feel put off by doctors who sound like ideologues from a different political tribe.

If the AMA really wants to do something for health equity they should stop trying to police language and instead support nurse practitioners, midwives, physician assistants, and other healthcare professionals who want to expand their practices, lobby for more physicians and an end to the absurd residency bottleneck, and support greater hospital competition. Physician heal thyself.

Photo Credit: Wikipedia.

Markets in everything

A Louisiana widow is left horrified at the news that her deceased husband was dissected in front of a live, paying audience after she donated his body to scientific research.

Elsie Saunders had carried out the wishes of her late husband, David Saunders, who wanted his body donated to help advance medical science, according to The Advocate. David Saunders, a World War II and Korean War veteran, died of COVID-19 on August 24 at the age of 98. Donating his body was his last act of patriotism, Elsie Saunders said.

But instead of being delivered to a research facility, David Saunders’ body ended up in a Marriott Hotel ballroom in Portland, Oregon, where DeathScience.org held an “Oddities and Curiosities Expo.” At the October 17 event, members of the public sat ringside from 9 am to 4 pm—with a break for lunch—to watch David Saunders’ body be carefully dissected. Tickets for the dissection sold for up to $500 per person…

Elsie Saunders learned of the dissection from a Seattle-based reporter at KING 5, who was investigating the event and tracked her down. A photojournalist who attended undercover for KING 5 had noted that the body had a bracelet with the typed name “David Saunders.”

“As far as I’m concerned, it’s horrible, unethical, and I just don’t have the words to describe it,” Elsie Saunders told The Advocate. “I have all this paperwork that says his body would be used for science—nothing about this commercialization of his death.”

Are medical students allowed to pay tuition?  Is “science” allowed to balance the books?  Here is the full story, via the excellent Samir Varma.

Addendum: Under other circumstances, it has been common to use donated bodies for crash test dummies.

Half Doses of Pfizer Work Well

New paper published in Vaccines from Polish group showing that half doses of Pfizer generate strong immune responses.

In the context of the ongoing COVID-19 pandemic, using a half-dose schedule vaccination can help to return to normalcy in a cost-efficient manner, which is especially important for low and middle-income countries. We undertook a study to confirm that in adults up to 55 years old, the humoral response to the half-dose (15 µg, 35 participants between 18 and 55 years old) and to the recommended dose (30 µg, 155 participants) in the two-dose three-week interval schedule would be comparable. Antibody levels were measured by the Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics, upper detection limit: 2570 BAU/mL) on the day of dose 2 of the vaccine and then 8–10 days later to assess peak response to dose 2. The difference in proportions between the participants who did and did not exceed the upper detection limit 8–10 days after dose 2 was not statistically significant (p = 0.152). We suggest that a half-dose schedule can help to achieve widespread vaccination coverage more quickly and cheaply.

See my previous piece A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca.

The economics of medical procedure innovation

Important NBER work from David Dranove, Craig Garthwaite, Christopher Heard, and Bingxiao Wu on an understudied intervention:

This paper explores the economic incentives for medical procedure innovation. Using a proprietary dataset on billing code applications for emerging medical procedures, we highlight two mechanisms that could hinder innovation. First, the administrative hurdle of securing permanent, reimbursable billing codes substantially delays innovation diffusion. We find that Medicare utilization of innovative procedures increases nearly nine-fold after the billing codes are promoted to permanent (reimbursable) from provisional (non-reimbursable). However, only 29 percent of the provisional codes are promoted within the five-year probation period. Second, medical procedures lack intellectual property rights, especially those without patented devices. When appropriability is limited, specialty medical societies lead the applications for billing codes. We indicate that the ad hoc process for securing billing codes for procedure innovations creates uncertainty about both the development process and the allocation and enforceability of property rights. This stands in stark contrast to the more deliberate regulatory oversight for pharmaceutical innovations.

Here are ungated copies.

“America Needs a New Scientific Revolution”

That is the title of the new Derek Thompson piece in The Atlantic.  Here is one excerpt:

The existing layers of bureaucracy have obvious costs in speed. They also have subtle costs in creativity. The NIH’s pre-grant peer-review process requires that many reviewers approve of an application. This consensus-oriented style can be a check against novelty—what if one scientist sees extraordinary promise in a wacky idea but the rest of the board sees only its wackiness? The sheer amount of work required to get a grant also penalizes radical creativity. Many scientists, anticipating the turgidity and conservatism of the NIH’s approval system, apply for projects that they anticipate will appeal to the board rather than pour their energies into a truly new idea that, after a 500-day waiting period, might get rejected. This is happening in an academic industry where securing NIH funding can be make-or-break: Since the 1960s, doctoral programs have gotten longer and longer, while the share of Ph.D. holders getting tenure has declined by 40 percent.

And:

First is the trust paradox. People in professional circles like saying that we “believe the science,” but ironically, the scientific system doesn’t seem to put much confidence in real-life scientists. In a survey of researchers who received Fast Grants, almost 80 percent said that they would change their focus “a lot” if they could deploy their grant money however they liked; more than 60 percent said they would pursue work outside their field of expertise, against the norms of the NIH. “The current grant funding apparatus does not allow some of the best scientists in the world to pursue the research agendas that they themselves think are best,” Collison, Cowen, and the UC Berkeley scientist Patrick Hsu wrote in the online publication Future in June. So major funders have placed researchers in the awkward position of being both celebrated by people who say they love the institution of science and constrained by the actual institution of science.

Much of the rest of the piece is a discussion of Fast Grants and also biomedical funding more generally.

ProPublica on FDA Delay

If you have been following MR for the last 18 months (or 18 years!) you won’t find much new in this ProPublica piece on FDA delay in approving rapid tests but, other than being late to the game, it’s a good piece. Two points are worth emphasizing. First, some of the problem has been simple bureaucratic delay and inefficiency.

In late May, WHPM head of international sales Chris Patterson said, the company got a confusing email from its FDA reviewer asking for information that had in fact already been provided. WHPM responded within two days. Months passed. In September, after a bit more back and forth, the FDA wrote to say it had identified other deficiencies, and wouldn’t review the rest of the application. Even if WHPM fixed the issues, the application would be “deprioritized,” or moved to the back of the line.

“We spent our own million dollars developing this thing, at their encouragement, and then they just treat you like a criminal,” said Patterson. Meanwhile, the WHPM rapid test has been approved in Mexico and the European Union, where the company has received large orders.

An FDA scientist who vetted COVID-19 test applications told ProPublica he became so frustrated by delays that he quit the agency earlier this year. “They’re neither denying the bad ones or approving the good ones,” he said, asking to remain anonymous because his current work requires dealing with the agency.

Recall my review of Joseph Gulfo’s Innovation Breakdown.

Second, the FDA has engaged in regulatory nationalism–refusing to look at trial data from patients in other countries. This is madness when India does it and madness when the US does it.

For example, the biopharmaceutical giant Roche told ProPublica that it submitted a home test in early 2021, but it was rejected by the FDA because the trials had been done partly in Europe. The test had compared favorably with Abbott’s rapid test, and received European Union approval in June. The company plans to resubmit an application by the end of the year.

A smaller company, which didn’t want to be named because it has other contracts with the U.S. government, withdrew its pre-application for a rapid antigen test with integrated smartphone-based reporting because it heard its trial data from India — collected as the delta variant was surging there — wouldn’t be accepted. Doing the trials in the U.S. would have cost millions.

Photo credit: MaxPixel.