Category: Medicine

Beware of coronavirus moralizing

That is the topic of my latest Bloomberg column, here is one excerpt:

Then there is the Swedish experiment, which has been the subject of a raging controversy. Here again, most moralizing is premature, even though the Swedes did make some clear mistakes, such as not protecting their nursing homes well enough. Sweden had a high level of early deaths, but both cases and deaths have since fallen to a very low level, even though Sweden never locked down. In the meantime, the Swedish economy has been among the least badly hit in Europe.

If the rest of Europe is badly hit by a second or third wave, and Sweden is not, Swedish policy suddenly will look much better. Alternatively, if Sweden experiences a second wave of infections as big as or bigger than those of its neighbors, it will look far worse.

In other words, it is too soon to tell.  I love to moralize about the moralizers!  Which I do more of at the link.

The Flynn Effect is stronger than you think

Despite the lack of effective treatments or preventive strategies, the dementia epidemic is on the wane in the United States and Europe, scientists reported on Monday.

The risk for a person to develop dementia over a lifetime is now 13 percent lower than it was in 2010. Incidence rates at every age have steadily declined over the past quarter-century. If the trend continues, the paper’s authors note, there will be 15 million fewer people in Europe and the United States with dementia than there are now…

Researchers at Harvard University in Cambridge, Mass., reviewed data from seven large studies with a total of 49,202 individuals. The studies followed men and women aged 65 and older for at least 15 years, and included in-person exams and, in many cases, genetic data, brain scans and information on participants’ risk factors for cardiovascular disease.

The data also include a separate assessment of Alzheimer’s disease. Its incidence, too, has steadily fallen, at a rate of 16 percent per decade, the researchers found. Their study was published in the journal Neurology.

In 1995, a 75-year-old man had about a 25 percent chance of developing dementia in his remaining lifetime. Now that man’s chance declined to 18 percent, said Dr. Albert Hofman, chairman of the department of epidemiology at the Harvard School of Public Health and the lead author of the new paper.

Interestingly, this decline seems to be confined to Europe and the United States.  Here is the Gina Kolata piece in the NYT.

The Hawaii bastion has fallen

“We must accept the new reality: The virus is widespread on Oahu,” said Anderson, noting that it’s becoming increasingly difficult for contact tracers to pinpoint the source of infection as the virus grows more and more prevalent.

Hawaii now has seen 2,448 positive cases of coronavirus since state health officials started reporting testing results in March. More than 500 of those cases were reported in the last seven days, and most of them are on Oahu.

Historically, about 1% to 2% of tests conducted in Hawaii have come back with positive COVID-19 results. But in recent days that percentage has crept up close to 5%.

“Any time it gets over 5%, there’s reason for concern,” Anderson said. “Some of the states where they’re having large outbreaks have high rates of over 10%. And, obviously, we don’t want to be there.”

The growing prevalence of COVID-19 in Hawaii could jeopardize the state’s ability to reopen public schools, bring college students back to campus and invite visitors to return to Hawaii, said Hawaii Gov. David Ige.

Here is the full story.  Of course it is much better to have cases now — when superior treatments are available — than back in March or April.  Still, the containment strategies that are supposed to work for the most part…do not in fact work.

Some doubts about medical ethics, and maybe that Russian vaccine is underrated

Most major questions in ethics are unsettled, though of course I have my own views, as do many other people.  I take that unsettledness as a fairly fundamental truth, I have been studying these matters for decades, and I even have several published articles in the top-ranked journal Ethics.

Now, if you take a whole group of people, give them medical licenses, teach them all more or less the same thing in graduate school, but not much other philosophy, and call it “medical ethics“…you have not actually gone much further.  Arguably you have retrogressed.

So when I hear people appeal to “medical ethics,” my intellectual warning bells go off.  To be sure, often I agree with those people, if only because I think contemporary American institutions often are not very flexible or able to execute effectively on innovations.  For instance, I didn’t think America could make a go at Robin Hanson’s variolation proposal, and so I opposed it.  “Medical ethics” seems to give the same instruction, though with less of a concrete institutional argument.

Still, the Lieutenant Colombo in me is bothered.  What about other nations?  Should we ever wish that they serve themselves up as medical ethics-violating guinea pigs, for the greater global good?

Medical ethics usually says no, or tries to avoid grappling with that question too directly.  But I wonder.

How about that Russian vaccine they will be trying in October?

To be clear, I won’t personally try it, and I don’t want the FDA to approve it for use in the United States.  But am I rooting for the Russians to try it this fall?  You betcha.  (Am I sure that is the correct ethical view?  No!  But I know the critics should not be sure either.)  I am happy to revise my views as further information comes in, but I see a good chance that  the attempt improves expected global welfare, and I think that is very often (but not always) a standard with strong and indeed decisive relevance.  And all the new results on cross-immunities imply that some pretty simple vaccines can have at least partial effectiveness.

Why exactly is “medical ethics” so sure this Russian vaccine is wrong other than that it violates “medical ethics”?  All relevant scenarios involve risk to millions of innocents, and I have not heard that Russians will be forced to take the vaccine.  The global benefits could be considerable, and I do note that the Russian vaccine scenario is the one that potentially spends down the reputational capital of various medical establishments.

Trying a not yet fully tested vaccine still seems wrong to many medical ethicists, even if the volunteers are compensated so they are better off in ex ante terms, as in some versions of Human Challenge Trials, an idea that (seemingly) has been elevated from “violating medical ethics” to a mere “problematic.”  Medical ethics claims priority over the ex ante Pareto principle, but I say we are back to the unsettled ethics questions on that one, but if anything with the truth leaning against medical ethics.

I find it especially strange when “medical ethics” is cited — often without further argumentation or explanation — on Twitter and other forms of social media as a kind of moral authority.  It then seems especially glaringly obvious that the moral consensus was never there in the first place, and that there is a gross and indeed now embarrassing unawareness of that underlying social fact.  It feels like citing Kant to the raccoon trying to claw through your roof.

I think medical ethics would not like this critique of medical ethics.  Yet I will be watching the Russian vaccine experiment closely.

Addendum: There is also biomedical ethics, but that would require a blog post of its own.  It is much more closely integrated with standard ethical philosophy, though it does not resolve any of the fundamental philosophical uncertainties.

Nursing home networks and Covid-19

We construct network measures of nursing home connectedness and estimate that nursing homes have, on average, connections with 15 other facilities. Controlling for demographic and other factors, a home’s staff-network connections and its centrality within the greater network strongly predict COVID-19 cases. Traditional federal regulatory metrics of nursing home quality are unimportant in predicting outbreaks, consistent with recent research. Results suggest that eliminating staff linkages between nursing homes could reduce COVID-19 infections in nursing homes by 44 percent.

That is from a new NBER working paper by M. Keith Chen, Judith A. Chevalier, and Elisa F. Long, and I am going to nominate this as one of the very best and most important papers of the year.

Cross-immunities at work again?

Health care workers may be less susceptible to COVID-19 infection than people in the communities they serve, according to surprising early data from an ongoing study at Hoag Memorial Hospital Presbyterian.

Of some 3,000 workers tested in May and June, only 1% had antibodies to the novel coronavirus in their blood, despite the fact that the Newport Beach hospital has cared for hundreds of COVID-19 patients.

That 1% is far lower than what has been found in wider communities. Some 4-6% of residents in Los Angeles, Santa Clara and Riverside counties had COVID antibodies when surveillance testing was done there over recent weeks and months.

“This is what surprises some people,” said Dr. Michael Brant-Zawadzki, principal investigator. “Despite the headlines you see saying health care workers are at higher risk of contracting the disease, we haven’t seen that. In fact, we’re seeing the reverse of that. The question is, why?”

Obviously some of this is PPE, mask-wearing, and the like.  But all of it?  Here is the Teri Sforza story, via Amihai Glazer.

Pandemics and persistent heterogeneity

It has become increasingly clear that the COVID-19 epidemic is characterized by overdispersion whereby the majority of the transmission is driven by a minority of infected individuals. Such a strong departure from the homogeneity assumptions of traditional well-mixed compartment model is usually hypothesized to be the result of short-term super-spreader events, such as individual’s extreme rate of virus shedding at the peak of infectivity while attending a large gathering without appropriate mitigation. However, heterogeneity can also arise through long-term, or persistent variations in individual susceptibility or infectivity. Here, we show how to incorporate persistent heterogeneity into a wide class of epidemiological models, and derive a non-linear dependence of the effective reproduction number R_e on the susceptible population fraction S. Persistent heterogeneity has three important consequences compared to the effects of overdispersion: (1) It results in a major modification of the early epidemic dynamics; (2) It significantly suppresses the herd immunity threshold; (3) It significantly reduces the final size of the epidemic. We estimate social and biological contributions to persistent heterogeneity using data on real-life face-to-face contact networks and age variation of the incidence rate during the COVID-19 epidemic, and show that empirical data from the COVID-19 epidemic in New York City (NYC) and Chicago and all 50 US states provide a consistent characterization of the level of persistent heterogeneity. Our estimates suggest that the hardest-hit areas, such as NYC, are close to the persistent heterogeneity herd immunity threshold following the first wave of the epidemic, thereby limiting the spread of infection to other regions during a potential second wave of the epidemic. Our work implies that general considerations of persistent heterogeneity in addition to overdispersion act to limit the scale of pandemics.

Here is the full paper by Alexei Tkachenko, et.al., via the excellent Alan Goldhammer.  These models are looking much better than the ones that were more popular in the earlier months of the pandemic (yes, yes I know epidemiologists have been studying heterogeneity for a long time, etc.).

From the comments, on coronaviruses

I am still waiting for the new conventional wisdom about what is happening to emerge, and I believe it will be as follows.

A particular ancestral betacoronavirus emerged in bats several decades ago with a special superpower, different from but conceptually not too distinct from HIV’s ability to rapidly mutate. This virus had the ability to easily spread out among many animal species and evolve among them through a standard slow process of mutation subject to selection pressures, but then to occasionally co-infect a single host and recombine to create a radically different variant (a “chimera,” although I think it’s better thought of as an “offspring.”). These offspring would occasionally be very deadly because they combined well-developed abilities that had evolved in separate lineages from the original ancestor evolving in separate species.

Eventually I think we will categorize all the recent betacoronavirus outbreaks (Sars-1, Sars-2, MERS) as part of this broader process, and require a vaccination strategy that can be quickly deployed against new recombinations from this original ancestral betacoronavirus as they randomly emerge from the primordial stew across many animal species, including ours. The evidence thus far points to recombinations resulting in the emergence of a distinct dangerous variant with some regularity.

This story also explains the existence of some preexisting immunity in much of the population to Sars-Cov-2, but substantial variation in what feature of Sars-Cov-2’s genetic code the immune system reacts to depending on whether the individual is known to have had SARS, MERS, or neither. In all likelihood, possibly many relatively nonlethal or even asymptomatic variants of the same betacoronavirus ancestor have been circulating undetected among human populations during this same 10-20 years, resulting in people people who have been exposed to different random bits of genetic material present in Sars-Cov-2.

Here is the link.  By the way, it turns out that smallpox is much older than we had thought (NYT).  Betting on origins being longer and deeper than other people expect is often the bet to make.

Which country has had the best response to the coronavirus?

I pick the United Kingdom, even though their public health response has been generally poor.  Why? Their researchers have discovered the single-best mortality-reducing treatment, namely dexamethasone (the cheap steroid), and the Oxford vaccine is arguably the furthest along.  In a world where ideas are global public goods, research matters more than the quality of your testing regime!

And the very recent results on interferon beta — still unconfirmed I should add — come from…the UK.

At the very least, the UK is a clear first in per capita terms.  Here are the closing two paragraphs:

It is fine and even correct to lecture the British (and the Americans) for their poorly conceived messaging and public health measures. But it is interesting how few people lecture the Australians or the South Koreans for not having a better biomedical research establishment. It is yet another sign of how societies tend to undervalue innovation — which makes the U.K.’s contribution all the more important.

Critics of Brexit like to say that it will leave the U.K. as a small country of minor import. Maybe so. In the meantime, the Brits are on track to save the world.

Here is my full Bloomberg column on that topic.  And if you wish to go a wee bit Straussian on this one, isn’t it better if the poor performers on public health measures — if there are going to be some — are (sometimes) the countries with the best and most dynamic biomedical establishments?  Otherwise all the panic and resultant scurry amounts to nothing.  When Mexico has a poor public health response to Covid-19, the world doesn’t get that much back in return.  In this regard, I suspect that biomedical innovation in the United States is more sensitive to internal poor performance on Covid-19 than is the case for Oxford.

A highly speculative version of the immunological dark matter hypothesis

The COVID-19 pandemic is thought to began in Wuhan, China in December 2019. Mobility analysis identified East-Asia and Oceania countries to be highly-exposed to COVID-19 spread, consistent with the earliest spread occurring in these regions. However, here we show that while a strong positive correlation between case-numbers and exposure level could be seen early-on as expected, at later times the infection-level is found to be negatively correlated with exposure-level. Moreover, the infection level is positively correlated with the population size, which is puzzling since it has not reached the level necessary for population-size to affect infection-level through herd immunity. These issues are resolved if a low-virulence Corona-strain (LVS) began spreading earlier in China outside of Wuhan, and later globally, providing immunity from the later appearing high-virulence strain (HVS). Following its spread into Wuhan, cumulative mutations gave rise to the emergence of an HVS, known as SARS-CoV-2, starting the COVID-19 pandemic. We model the co-infection by an LVS and an HVS and show that it can explain the evolution of the COVID-19 pandemic and the non-trivial dependence on the exposure level to China and the population-size in each country. We find that the LVS began its spread a few months before the onset of the HVS and that its spread doubling-time is \sim1.59\pm0.17 times slower than the HVS. Although more slowly spreading, its earlier onset allowed the LVS to spread globally before the emergence of the HVS. In particular, in countries exposed earlier to the LVS and/or having smaller population-size, the LVS could achieve herd-immunity earlier, and quench the later-spread HVS at earlier stages. We find our two-parameter (the spread-rate and the initial onset time of the LVS) can accurately explain the current infection levels (R^2=0.74); p-value (p) of 5.2×10^-13). Furthermore, countries exposed early should have already achieved herd-immunity. We predict that in those countries cumulative infection levels could rise by no more than 2-3 times the current level through local-outbreaks, even in the absence of any containment measures. We suggest several tests and predictions to further verify the double-strain co-infection model and discuss the implications of identifying the LVS.

That is a new paper from Hagai and Ruth Perets, another link here, via Yaakov.

The Thai coronavirus paradox

Dr. Wiput Phoolcharoen, a public health expert at Chulalongkorn University in Bangkok who is researching an outbreak of the coronavirus in Pattani in southern Thailand, noted that more than 90 percent of those who tested positive there were asymptomatic, much higher than normal.

“What we are studying now is the immune system,” he said.

Dr. Wiput said Thais and other people from this part of Southeast Asia were more susceptible to certain serious cases of dengue fever, a mosquito-borne virus, than those from other continents.

“If our immune systems against dengue are so bad, why can’t our immune system against Covid be better?” he asked.

Here is more from the NYT, good to see coverage of this.  Finally we are getting somewhere.

Swedish update, and which places need to fear second waves?

Your recent question intrigued me. Do you have any new info/opinions on what’s happening in Sweden? Despite no mask wearing, continued indoor dining (at least judging from recent photos on instagram), their case AND death daily counts are plummeting (looks like an inverse exponential). This would also explain excess deaths returning to normal throughout US. Bizarrely, my cursory reading of Swedish newpapers online did not result in any recent articles discussing the dramatic decline in cases there!

One theory circulating is they achieved herd immunity on the math: 10x true seroprevalence (from CDC tests in US) * 2x true immunity (from Tcell things not measured by antibody tests that I don’t fully understand) * 0.75% reported case penetration * 2x for relatively low tests per capita rate = 30% true immunity (likely much higher in densest areas where spread would be much faster resulting in maybe >70% immunity in Stockholm). This puts them r0 < 1.

The nice thing about this hypothesis is that it’s easily falsifiable. If true immunity rates are 20x reported case load (dropping last 2x factor since test rate higher in US), then Florida should have just gotten to the 1.4% necessary to trigger similar immunity in dense cities and from now on, cases per day should follow an inverse exponential.

This would also explain why NYC has not seen a resurgence despite very similar reopening as SF and LA – they achieved dense herd immunity in May and thus the subsequent decline in reported cases was driven by herd immunity rather than more strict closures or mask compliance, reversing either of those factors now doesn’t reverse immunity. To be clear, I’m not disputing that distancing or mask wearing works – they do. But so does infecting everyone quickly. No value judgements on what’s the better policy decision here, just trying to make a predictive statement.

At least, one can hope!

That is my email from Mayank Gupta.  In my view, some version of this view is looking more true with each passing day.  We also are not seeing second waves in hard-hit northern Italy.  Still, many surprises remain and we should not leap to premature conclusions.

To be clear, I was and still am pro-lockdown (without regrets), pro-mask, pro-testing, and I believe Denmark followed a better path than did Sweden.  Long-term damage (rather than death) still may be a significant risk, and furthermore many parts of the world may be far more vulnerable than the United States.  Still, you need to put all of the moralizing and partisanship aside and ask what we are learning from the new data, and I think Mayank Gupta has put it (probabilistically) very well.  And see this related Atlantic piece, though I would have some quibbles with it.  And here is a bit more commentary on the new T-cell results.

In any case, always be prepared to revise!  I believe that within a month we will have a much better sense of these questions.

Addendum: You will note these hypotheses also significantly raise the probability of much earlier animal-to-human transmission, especially in Southeast Asia.  A very good baseline principle for reasoning is simply “Origins usually go back longer and earlier than what you first might think!”

Second addendum: If you go back to March, leading epidemiologist Michael Osterhalm argued: “We conservatively estimate that this could require 48 million hospitalizations, 96 million cases actually occurring, over 480,000 deaths that can occur over the next four to seven months with this situation.”  Covid-19 has been terrible, and the performance of the executive branch (and many governors) absymal, but do those look like good predictions right now?  (Hospitalizations for instance have yet to hit 250k.)  If not, why not?  How hard have you thought about this question?  (Added note: one correspondent suggests that Osterhalm misspoke and in fact meant 4.8 million hospitalizations — note that still would be off by quite a large margin, almost a factor of twenty.)

Our regulatory state is failing us, antibodies edition

It might be the next best thing to a coronavirus vaccine.

Scientists have devised a way to use the antibody-rich blood plasma of COVID-19 survivors for an upper-arm injection that they say could inoculate people against the virus for months.

Using technology that’s been proven effective in preventing other diseases such as hepatitis A, the injections would be administered to high-risk healthcare workers, nursing home patients, or even at public drive-through sites — potentially protecting millions of lives, the doctors and other experts say.

The two scientists who spearheaded the proposal — an 83-year-old shingles researcher and his counterpart, an HIV gene therapy expert — have garnered widespread support from leading blood and immunology specialists, including those at the center of the nation’s COVID-19 plasma research.

But the idea exists only on paper. Federal officials have twice rejected requests to discuss the proposal, and pharmaceutical companies — even acknowledging the likely efficacy of the plan — have declined to design or manufacture the shots, according to a Times investigation. The lack of interest in launching development of immunity shots comes amid heightened scrutiny of the federal government’s sluggish pandemic response.

Here is more from the LA Times, substantive throughout, via Anecdotal.

Too many autistic adults are denied basic rights

That is the topic of my latest Bloomberg column, here is one excerpt:

Some of the very worst treatment of the vulnerable is hardly being discussed. There is an entire category of American adults being denied almost all of their basic legal rights: to hold a job, choose a residence, determine their health care, enter into contracts and even decide what to do with their own body. These are adults under legal guardianship — a court-imposed process, in Ohio as elsewhere, “by which a person is relieved of the right to make personal life decisions and another is appointed to make those decisions on that person’s behalf.”

Among the adults who have lost such rights, or live under the fear that they will, are those with autism. It is entirely possible that they will end up in guarded and segregated communities, often against their will.

Perhaps you think many of these individuals are unable to care for themselves and therefore their full rights cannot be respected. To whatever extent that may be true, it is not a reason for trampling on human rights. And even if you believe it is, you must concede that the legal system is prone to horrible misjudgments and mistakes.

After recent revelations about institutional racism, it is hard to believe that prejudices do not affect decisions about guardianship. The justice system is already heavily biased in favor of plea bargains, in effect favoring efficiency over constitutional rights. And even when there is no bias, there is the reality of simple error — which are common enough in hospitals, where the stakes are much higher.

Definitely recommended, do read the whole thing.  And don’t forget this:

When it comes to guardianship, is there any reason to be so sure that liberty-protecting institutions are in place? Especially since basic information is so hard to come by? As both a people and a polity, Americans do not always behave best “when no one is watching.”

Overall it is remarkable to me how little good information, or for that matter argumentation, is available on this topic.

A highly qualified reader emails me on heterogeneity

I won’t indent further, all the rest is from the reader:

“Some thoughts on your heterogeneity post. I agree this is still bafflingly under-discussed in “the discourse” & people are grasping onto policy arguments but ignoring the medical/bio aspects since ignorance of those is higher.

Nobody knows the answer right now, obviously, but I did want to call out two hypotheses that remain underrated:

1) Genetic variation

This means variation in the genetics of people (not the virus). We already know that (a) mutation in single genes can lead to extreme susceptibility to other infections, e.g Epstein–Barr (usually harmless but sometimes severe), tuberculosis; (b) mutation in many genes can cause disease susceptibility to vary — diabetes (WHO link), heart disease are two examples, which is why when you go to the doctor you are asked if you have a family history of these.

It is unlikely that COVID was type (a), but it’s quite likely that COVID is type (b). In other words, I expect that there are a certain set of genes which (if you have the “wrong” variants) pre-dispose you to have a severe case of COVID, another set of genes which (if you have the “wrong” variants) predispose you to have a mild case, and if you’re lucky enough to have the right variants of these you are most likely going to get a mild or asymptomatic case.

There has been some good preliminary work on this which was also under-discussed:

You will note that the majority of doctors/nurses who died of COVID in the UK were South Asian. This is quite striking. https://www.nytimes.com/2020/04/08/world/europe/coronavirus-doctors-immigrants.html — Goldacre et al’s excellent paper also found this on a broader scale (https://www.medrxiv.org/content/10.1101/2020.05.06.20092999v1). From a probability point of view, this alone should make one suspect a genetic component.

There is plenty of other anecdotal evidence to suggest that this hypothesis is likely as well (e.g. entire families all getting severe cases of the disease suggesting a genetic component), happy to elaborate more but you get the idea.

Why don’t we know the answer yet? We unfortunately don’t have a great answer yet for lack of sufficient data, i.e. you need a dataset that has patient clinical outcomes + sequenced genomes, for a significant number of patients; with this dataset, you could then correlate the presences of genes {a,b,c} with severe disease outcomes and draw some tentative conclusions. These are known as GWAS studies (genome wide association study) as you probably know.

The dataset needs to be global in order to be representative. No such dataset exists, because of the healthcare data-sharing problem.

2) Strain

It’s now mostly accepted that there are two “strains” of COVID, that the second arose in late January and contains a spike protein variant that wasn’t present in the original ancestral strain, and that this new strain (“D614G”) now represents ~97% of new isolates. The Sabeti lab (Harvard) paper from a couple of days ago is a good summary of the evidence. https://www.biorxiv.org/content/10.1101/2020.07.04.187757v1 — note that in cell cultures it is 3-9x more infective than the ancestral strain. Unlikely to be that big of a difference in humans for various reasons, but still striking/interesting.

Almost nobody was talking about this for months, and only recently was there any mainstream coverage of this. You’ve already covered it, so I won’t belabor the point.

So could this explain Asia/hetereogeneities? We don’t know the answer, and indeed it is extremely hard to figure out the answer (because as you note each country had different policies, chance plays a role, there are simply too many factors overall).

I will, however, note that this the distribution of each strain by geography is very easy to look up, and the results are at least suggestive:

  • Visit Nextstrain (Trevor Bedford’s project)
  • Select the most significant variant locus on the spike protein (614)
  • This gives you a global map of the balance between the more infective variant (G) and the less infective one (D) https://nextstrain.org/ncov/global?c=gt-S_614
  • The “G” strain has grown and dominated global cases everywhere, suggesting that it really is more infective
  • A cursory look here suggests that East Asia mostly has the less infective strain (in blue) whereas rest of the world is dominated by the more infective strain:
  • image.png

– Compare Western Europe, dominated by the “yellow” (more infective) strain:

image.png

You can do a similar analysis of West Coast/East Coast in February/March on Nextstrain and you will find a similar scenario there (NYC had the G variant, Seattle/SF had the D).

Again, the point of this email is not that I (or anyone!) knows the answers at this point, but I do think the above two hypotheses are not being discussed enough, largely because nobody feels qualified to reason about them. So everyone talks about mask-wearing or lockdowns instead. The parable of the streetlight effect comes to mind.”