Category: Medicine

The Omission-Commission Error is Deadly

Britain will start a human challenge trial in January.

The Sun: Imperial College said its joint human challenge study involves volunteers aged 18 to 30, with the project starting in January – and results expected in May.

Initially, 90 volunteers will be given a dose of an experimental nasal vaccine.

They’ll then be deliberately infected with Covid-19.

But this is really just the first part of an excessively cautious study designed to “discover the smallest amount of virus it takes to cause a person to develop Covid-19 infection.” Moreover:

… it’s taken a few months to come to fruition, as before any research could begin the study had to be approved by ethics committees and regulators.

The omission-commission error is deadly. Notice that giving less than one hundred volunteers the virus (commission) is ethically fraught and takes months of debate before one can get approval. But running a large randomized controlled trial in which tens of thousands of people are exposed to the virus is A-ok even though more people may be infected in the latter case than the former and even though faster clinical trials could save many lives. Ethical madness.

How to improve and speed up vaccine allocation, from my email

One issue I haven’t seen discussed is slow throughput of the Vaccine administration, due to a combination of inefficient binning/allocation of distributed vaccines, hesitation to take the vaccine, lack of a central database of available appointments for vaccination, and those time slots potentially going empty if a front line worker misses their appointment, and when there’s no standby/waitlist for people to receive it.

These seems like a use case for a priority queue/heap, which would allow high priority folks to join the queue late but be bumped up to their appropriate priority if they wanted the vaccine, while also allowing those who want the vaccine but are not currently prioritized to get it if there are unallocated supplies.

If prioritization is done (cdc guidelines or not) by restricting who can get it during a particular time period, then it’s guaranteed that throughout won’t be maximized, as all appointment slots won’t be necessarily filled (given the hesitance I’ve heard from people across different levels of education and socioeconomic status) by the allowed demographics at each office where vaccines are available. Meanwhile, there will be those who would gladly take it in an instant who aren’t allowed.

I worry that slow throughput and bad prioritization vaccine administration will keep hospitals indefinitely full, hemorrhaging money, and will thus require a bailout, which I expect will come with medicare4all-style strings attached.

That is from Abhi C., a loyal MR reader.

Vaccine incentives matter (from my email)

I am a physician in private practice in [redacted]. We have just been approved to order and administer the vaccine to tier-appropriate patients. Medicare has approved a payment of 18$ for the first shot and 28$ for the second. As far as we can determine we will not be allowed to bill for an office visit so that is the entire amount we will receive for registering the patients, screening then for covid outside of the office, taking their vital signs, taking a history to see if there are any contraindications to the vaccine, administering the vaccine, observing them in the clinic for a minimum of 15 minutes up to 30 minutes depending on their history, and recalling them in 28 days and going through most of the same procedure again, minus the registration and history. There is also an extensive regime of recording and reporting all vaccination data daily to the state government. We had anticipated hiring someone to manage this new service due to the amount of new work that is required. At this rate we might be able to give 10 shots an hour in each of our 3 clinics if we see no other patients for illness, injury, or covid testing.

Do I need to say that we cannot possibly afford to do this for the reimbursement offered. The alternative is for patients to receive the vaccine in some state funded site or clinic. That may take a very long time to roll out.

We need many more economists complaining about this, right?  Other than John Cochrane, where will we find them? Why do we not find them?

Dr. Fauci, Straussian

Recently, a figure to whom millions of Americans look for guidance — Dr. Anthony S. Fauci, an adviser to both the Trump administration and the incoming Biden administration — has begun incrementally raising his herd-immunity estimate.

In the pandemic’s early days, Dr. Fauci tended to cite the same 60 to 70 percent estimate that most experts did. About a month ago, he began saying “70, 75 percent” in television interviews. And last week, in an interview with CNBC News, he said “75, 80, 85 percent” and “75 to 80-plus percent.”

In a telephone interview the next day, Dr. Fauci acknowledged that he had slowly but deliberately been moving the goal posts. He is doing so, he said, partly based on new science, and partly on his gut feeling that the country is finally ready to hear what he really thinks.

Hard as it may be to hear, he said, he believes that it may take close to 90 percent immunity to bring the virus to a halt — almost as much as is needed to stop a measles outbreak.

Asked about Dr. Fauci’s conclusions, prominent epidemiologists said that he might be proven right…

Dr. Fauci said that weeks ago, he had hesitated to publicly raise his estimate because many Americans seemed hesitant about vaccines, which they would need to accept almost universally in order for the country to achieve herd immunity.

Here is the full NYT story.  A few points:

1. Surely Straussianism by now should be persuasive as a general theory.

2. Fauci is idolized by many as a kind of anti-Trump, but he is a terrible risk communicator, as evidenced also by his recent attacks on some of the “lesser” vaccines (which still would work if applied collectively).  Not to mention his earlier remarks on masks, and also the mid-March safety of cruises.  How a person understands Fauci is in fact a pretty good litmus test.

3. Should you be trusting everything the insiders are telling you about FDA processes?

4. I genuinely do not know what the herd immunity threshold is, but I assure you I am trying to tell you the truth on this one (and other matters).  My Straussianism is not a normative theory of my own communication, but rather a positive theory of how the world works, and it has been vindicated once again.

New blood-test device monitors blood chemistry continually

“A blood test is great, but it can’t tell you, for example, whether insulin or glucose levels are increasing or decreasing in a patient,” said Tom Soh, a professor of electrical engineering and of radiology at Stanford. “Knowing the direction of change is important.”

Now, Soh, in collaboration with Eric Appel, an assistant professor of materials science and engineering, and colleagues have developed a technology that can provide this crucial piece of missing information. Their device, which they’ve dubbed the “Real-time ELISA,” is able to perform many blood tests very quickly and then stitch the individual results together to enable continuous, real-time monitoring of a patient’s blood chemistry. Instead of a snapshot, the researchers end up with something more like a movie.

In a new study, published in the journal Nature Biomedical Engineering, the researchers used the device to simultaneously detect insulin and glucose levels in living diabetic laboratory rats. But the researchers say their tool is capable of so much more because it can be easily modified to monitor virtually any protein or disease biomarker of interest…

Technologically, the system relies upon an existing technology called Enzyme-linked Immunosorbent Assay – ELISA (“ee-LYZ-ah”) for short. ELISA has been the “gold standard” of biomolecular detection since the early 1970s and can identify virtually any peptide, protein, antibody or hormone in the blood. An ELISA assay is good at identifying allergies, for instance. It is also used to spot viruses like HIV, West Nile and the SARS-CoV-2 coronavirus that causes COVID-19.

“We do ELISA continuously,” Soh said.

The Real-time ELISA is essentially an entire lab within a chip with tiny pipes and valves no wider than a human hair. An intravenous needle directs blood from the patient into the device’s tiny circuits where ELISA is performed over and over.

Here is the full story, via Malinga Fernando.

The Tony Blair “one dose” idea

Here is the source, of course Alex Tabarrok was there first.  For now give everyone one dose rather than two, and enjoy the partial but more broadly spread protection.  Here are the reactions from two epidemiologists:

Professor Wendy Barclay, from the department of infectious disease at Imperial College London, said Mr Blair’s idea was interesting but agreed it was “too risky” to try without further evidence.

And Professor Neil Ferguson, also from Imperial, added that the UK regulator had authorised the vaccine on the basis that people would receive two doses.

Administering one dose only would require “an entirely different regulatory submission”, he told a Commons committee.

A Department of Health and Social Care spokesperson said: “Over the coming weeks and months, the rate of vaccinations will increase as more doses become available and the programme continues to expand.”

Where are their cost-benefit analyses?  Letting people get infected at current and indeed accelerating rates is also “too risky,” yes?  Is there an epidemiologist or public health expert out there willing to show his or her work, either for or against this idea?  A genuine query, and of course comments are open.  How about one dose for Moderna only?  If we are to defer to their expertise, they do actually have to step up and be the experts, right?

Update on the new Covid-19 strain

Here is a very good article with many points, here are two in particular that caught my attention:

People with a weakened immune system may give the virus this opportunity, as Gupta’s data show. More evidence comes from a paper published in The New England Journal of Medicine on 3 December that described an immunocompromised patient in Boston infected with SARS-CoV-2 for 154 days before he died. Again, the researchers found several mutations, including N501Y. “It suggests that you can get relatively large numbers of mutations happening over a relatively short period of time within an individual patient,” says William Hanage of the Harvard T.H. Chan School of Public Health, one of the authors. (In patients who are infected for a few days and then clear the virus, there simply is not enough time for this, he says.) When such patients are given antibody treatments for COVID-19 late in their disease course, there may already be so many variants present that one of them is resistant, Goldstein says.

And:

These could impact the binding of the virus to human cells and also its recognition by the immune system, Farrar says. “These South African mutations I think are more worrying than the constellation of the British variant.” South African hospitals are already struggling, he adds. “We’ve always asked, ‘Why has sub-Saharan Africa escaped the pandemic to date?” Answers have focused on the relative youth of the population and the climate. “Maybe if you just increase transmission a bit, that is enough to get over these factors,” Farrar says.

Developing…the speed premium of course is rising…

School Closures During the 1918 Flu Pandemic

The COVID-19 pandemic has reignited interest in responses to the 1918-19 influenza pandemic, the last comparable U.S. public health emergency. During both pandemics, many state and local governments made the controversial decision to close schools. We study the short- and long-run effects of 1918-19 pandemic-related school closures on children. We find precise null effects of school closures in 1918 on school attendance in 1919-20 using newly collected data on the exact timing of school closures for 168 cities in 1918-19. Linking affected children to their adult outcomes in the 1940 census, we also find precise null effects of school closures on adult educational attainment, wage income, non-wage income, and hours worked in 1940. Our results are not inconsistent with an emerging literature that finds negative short-run effects of COVID-19-related school closures on learning. The situation in 1918 was starkly different from today: (1) schools closed in 1918 for many fewer days on average, (2) the 1918 virus was much deadlier to young adults and children, boosting absenteeism even in schools that stayed open, and (3) the lack of effective remote learning platforms in 1918 may have reduced the scope for school closures to increase socioeconomic inequality.

That is from a new paper by Philipp Ager, Katherine Eriksson, Ezra Karger, Peter Nencka, and Melissa A. Thompson.  This is very good and important work, though you will find some Denkfehler in the second half of the abstract, namely confusing short- and long-run (is it so appalling to consider that “school” isn’t always “useful learning” over a 20-year time horizon?) and confusing inequality with absolute performance.  Those are simple points people, you are being misled by your ideology.

First Dose First

Writing on twitter Keith Klugman, world expert on infectious diseases and director of the Gates Foundation Pneumonia program, supports a policy I have argued for–First Doses First.

First doses of Pfizer/Moderna vaccines are 90%+ effective after 14 days. Most high risk lives will be saved by giving all these limited early supplies of vaccine as first doses – second doses can be given later if first dose effectiveness wanes or when supply improves

Here’s a way of thinking about this policy. Suppose you are scheduled for your second dose of the Pfizer or Moderna vaccine but you have the option of giving your second dose to your spouse as their first dose. Would you?

If the answer is yes then can you ethically deny this to someone else’s spouse?

Keep in mind that we have at least three more vaccines that could be available in as little as 12 weeks, Astra-Zeneca, Johnson & Jonson and Novavax. We are also pushing for more doses from Pfizer and we should be willing to pay top-dollar for those doses. As those vaccines come online we can deliver second doses.

Addendum: If you are 75 and your spouse is 25 then maybe you wouldn’t give your second dose to your spouse and that too ought to help us think about the larger questions of allocation.

The Tremendous Success of Operation Warp Speed

I am annoyed at Fauci for the second time, this time for dissing the AZ vaccine:

But even if the vaccine ends up being approved, it will probably only have an efficacy of 60 to 70 percent. “What are you going to do with the 70 percent when you’ve got two (vaccines) that are 95 percent? Who are you going to give a vaccine like that to?” Anthony Fauci, the leading American expert on vaccines, recently wondered.

This attitude is counter-productive. As I wrote earlier:

In the big picture, the efficacious of a vaccine doesn’t matter per se what matters is getting to herd immunity. If you have a less efficacious vaccine you need to vaccinate more people but herd immunity is herd immunity, i.e. vaccines mostly protect people not because they are efficacious but because we reach herd immunity.

As a result, it can be much better to start vaccinating now with a 70% efficacious vaccine than wait for a 95% efficacious vaccine–thus, we need to encourage early vaccination. Indeed the AZ vaccine ought to be approved immediately (I predict the UK will approve by next week) and be made available to anyone who doesn’t want to wait for another vaccine.

For the next year or two, we will be operating under conditions of scarcity and we need to use every tool at our disposal. A 70% effective vaccine is great, well above what the FDA required and better than the flu vaccine. If you live in a country in which everyone has been vaccinated you won’t give a damn whether they were vaccinated with a 95% effective vaccine or a 70% effective vaccine–both will give you nearly 100% safety and allow life to return to normal.

The new Covid strain and its policy implications

Here is one account, please note this investigation is in its early days:

“An increase in R of 0.4 or greater is extremely bad news. During the national lockdown in November the best we could achieve was an R value of somewhere between 0.8 and 1.0 around the UK,” said Prof Hunter. “What this means is that even if we went back to the lockdown it would still not be enough to bring the R value down to less than 1.0.”

Note also it is very likely the new mutation already has spread well beyond the UK.  And with compounding, an R increase of 0.4 is really bad as time passes.

If this all is true, what are the policy implications?  First, a lockdown with no pending vaccine will only postpone problems, a’ la the herd immunity theorists.

Second, we do have vaccines and so in any plausible model faster viral spread implies a faster timetable for vaccine approval and distribution.  And it implies we should have been faster to begin with.

If you used to say “we were just slow enough,” you now have to revise that opinion and believe that greater speed is called for, both prospectively and looking backwards.

In any plausible model.

If Godzilla is faster than you had thought, you need to start running away sooner.  And you needed to have started running away sooner.  In any plausible model.

In any plausible model.

Yet somehow I do not expect the rooftops to be so crowded over the next few days.

What should I ask Patricia Fara?

I will be doing a Conversation with her, here is part of her Wikipedia page:

Patricia Fara is a historian of science at the University of Cambridge. She is a graduate of the University of Oxford and did her PhD at the University of London

Her areas of particular academic interest include the role of portraiture and art in the history of science, science in the 18th century England during the Enlightenment and the role of women in science. She has written about numerous women in science, mathematics, engineering, and medicine including: Hertha AyrtonLady Helen GleichenMona Chalmers WatsonHelen Gwynne-VaughanIsabel Emslie HuttonFlora MurrayIda MacleanMarie Stopes, and Martha Annie Whiteley. She has argued for expanded access to childcare as a means of increasing the retention of women in science. She has written and co-authored a number of books for children on science. Fara is also a reviewer of books on history of science. She has written the award-winning Science: A Four Thousand Year History (2009) [and Erasmus Darwin: Sex, Science, and Serendipity (2012). Her most recent book is A Lab of One’s Own: Science and Suffrage in the First World War” (2017). In 2013, Fara published an article in Nature (journal), stressing the fact that biographies of female scientists perpetuate stereotypes.

And she has a new book coming out on Isaac Newton.  So what should I ask her?