Sunday, July 26, 2020

We're trying to make our SARS-2 tests better than we should

Ok, that's a somewhat provocative title but I think it's basically accurate.  During this pandemic the US in particular has had a problem with erring towards the side of better, more expensive tests when what we've really needed has been cheaper tests.

An inauspicious start


The US got off to a really bad start testing for Coronavirus.  Scott Gottlieb was head of the FDA until a year ago and, in contrast to many other Trump appointees, was generally acknowledged as very competent.  Back in February he put together a Twitter thread outlining what was happening in terms of testing which I'll summarize here.  Normally hospitals with PCR machines, which is most medium sized or larger ones, can just go ahead and develop their own tests for viruses.  However the CDC thought it would be important to have widely available testing kits which would be of a higher quality than what hospitals could do themselves.  So they asked HHS to declare that Covid-19 was a public health emergency so they would be allowed to start working on their kits, which HHS did on January 31st.  But because a public health emergency was declared around Covid hospitals were no longer allowed to do their own testing.

That would have been fine if the CDC was able to produce a test quickly but of course we all know it wasn't.  Rather than trying to implement the simple one part test that the WHO recommended and which was essentially what hospitals would have done themselves in the absence of a declaration of emergency it developed a more complicated three part test.  That more complicated test took several weeks to develop.  And as we all know that more complicated test just didn't work.  Well, the first part which detected SARS-2 worked.  The second part which detected SARS-2 as well through a different method worked for most hospitals but not for others.  But it was the third part of the test that really caused problems.  That part was there to see if the patient might have another infection that might be confusing matters.  And the validation step for that third part had some faulty reagents that failed to validate the test at basically all the hospitals that got the CDC testing kits. 

If the testing was done at some third world country then the CDC could probably have just told hospitals to use the first part and ignore the rest.  But in the US we expect well tested medicine and the FDA hadn't approved that test procedure.  So all those test kits couldn't be used.  We did continue to have hospitals ship samples to the CDC to be tested by them but the bandwidth there was very limited.  This was the era when you could only get tested in the US if you had recently been to China.  Because there wasn't enough testing capacity at the time for anything like the number of tests that were needed some arbitrary criterion had to be used to winnow them down and I suppose that one was better than assigning testing resources by lottery.

By February 29th, a month after the emergency was declared, the FDA decided it would allow about 5,000 of the most sophisticated laboratories in the US to start doing their own testing and on March 16th they decided that basically any certified laboratory should be allowed to test for Covid.

Here's a more detailed timeline of all of this for the curious.

In retrospect I think it clearly wasn't true that
 "In the U.S., we have policies in place that strike the right balance during public health emergencies of ensuring critical independent review by the scientific and public health experts and timely test availability.  The CDC test is a high-quality test, and it’s important to remember that false negatives or positives can be detrimental to making sure we are treating patients early, without delay, and also not quarantining healthy individuals.”
as FDA Commissioner Stephen Hahn said.  We clearly error too far on the side of test quality.  If you only have a hundredth of the number of tests you need your tests effectively have a 99% false negative rate and nothing we could have ended up with would have been nearly that bad.

Current problems

We've solved those problems that plagued our early response but there are still issues.  As contact tracing efforts in the US have ramped up we've started to get backlogs delays in getting results back from tests have started to increase.  And that's a real problem.

When you first get infected with Covid-19 you, of course don't notice anything at first.  But after a few days (or possibly longer) the amount of virus in your respiratory system starts to ramp up very quickly.  Eventually they hit a peak and start slowly going down.  And generally only at this point, most of a day after peak infectiousness, do you start to develop symptoms.  That's what makes this disease so much harder to contain than SARS was.  

The ideal test would be cheap and plentiful enough that you could test everybody every day.  It would give you a result quickly after taking the test.  It wouldn't give false positives or false negatives.  And it would be sensitive enough to detect an infection no matter how early in its progression.  There doesn't seem to be any technology that can give us all of that but there are potentially better tradeoffs we could make.

PCR works by taking a sample that might have viral RNA and, if it is present, doubling the amount again and again in cycles until the level of RNA is detectable.  How many cycles it takes, the cycle threshold or CT, is a measure of how much viral DNA there was.  PCR machines can generally go for up to 40 cycles leading to them being able to detect very small levels of virus.  But they're big machines and the samples have to get to them and it often takes at least a day to get the result back.

On the other hand we've long used a different sort of test for things like the measles, flu, or pregnancy tests.  These have antigens for specific proteins and change color in contact with them. However, they do come with a downside.  Without replication they are less sensitive than a PCR test, maybe only going down to a CT of 35 or so.  This means that they will miss some infections that PCR test would catch.  But that probably isn't as important as it looks.

To have a reasonable chance of infecting someone else you need a certain amount of virus, probably a CT value of less than 30 or 25 for a reasonable chance - we aren't sure exactly where the cutoff would be yet.  So while the antigen will miss a good fraction of infections it won't miss any more infectious people than a PCR test would.  As virus levels are initially climbing there's a window where a PCR test can detect an infection but an antigen test can't.  However, people generally spend less time in this window than the difference in turnaround time between a PCR test and an antigen test.  So if someone is being continuously tested with both methods the PCR machine will get a sample it can detect from them first but they'll hear back from the antigen test before that.

And of course antigen tests can be much, much cheaper than PCR tests, possibly less than $10 in mass manufacture, and could be theoretically self administered every day whereas PCRs require trained personnel that can't really be scaled like that.

There are cases where PCR is better.  If someone has been sick with pneumonia for over a week and just taken a turn for the worse and ends up at an ER then by that point detecting the virus may require a PCR test.  In a strictly medical sense of treating a patient at a hospital they work better.  But in a public health sense of halting the spread of a disease within a community sense they're worse.

We've already seen a lot of negative media coverage about faster but less sensitive tests.  FDA probes accuracy issue with Abbott’s rapid coronavirus testCoronavirus Antibody Tests: Can You Trust the Results?  These pieces correctly point out that there are infections these test wouldn't detect but not the reasons we shouldn't care.  So there's political pressure not to approve these because the reasoning takes a little while to explain.

Also, the paradigm the FDA works in is mostly hospital treatment, public health interventions aren't central to what it does.  So I worry that if some test is great for public health purposes but poor for medical purposes and some confused intern could possibly use it instead of the right test in a medical setting then the FDA won't consider approving it.

But I really hope I'm wrong because this could be a very important intervention.  I just don't think history is on our side.

Sunday, April 12, 2020

The very long run for SARS Covid 2

Many of the worst pandemics that afflict us are from pathogens that don't normally prey on humans.  Probably the most famous pandemic in history was the Black Death.  On the steppe it lives in marmots which it has reached an equilibrium with.  But sometimes a flea transmits it to a rat.  The rat gives the disease to its other fleas and then dies.  Those fleas go to other rats and spread the disease.  When all the rats are dead the fleas find their way to humans instead.  The disease isn't quite as lethal in humans as it is in rats but it still killed a large fraction of the people who got it before the rise of antibiotics.

That's pretty typical of zoonotic diseases, or diseases that spread from one species to another.  Most of the time they're just ineffective and can't survive or are mopped up easily by our automatic immune system without us noticing.  But if they succeed they're often the most dangerous diseases that can afflict us because we're not in equilibrium with them.

There was a great essay in Aeon a while back, Coincidental Killers, that focused on deadly bacteria that mostly just aren't interested in humans and evolved properties that ended up being deadly in humans by accident.  Sometimes people go swimming in the wrong spot, get bacterial water up into their nose where the olfactory bulb comes in, and the bacteria discover that they can reproduce feeding on neurons and without treatment the victim dies.  This is bad for the bacterium, when the person dies all the bacteria of that lineage die out too.  But they weren't evolved to infect humans, they were evolved to live in their watery environment and it was just accident that they could live in and feed on a human brain too.

Very deadly diseases that can actually be transmitted from human to human are also in a similar position. If they burn too fast eventually all the humans they can reach will be either dead or immune and then what do they do?  Pathogens that spend a long time with humans tend to evolve to either be less virulent or to at least kill their hosts more slowly like AIDS or leprosy.  This isn't to say that diseases want to be perfectly safe if they're good at spreading, see the flu, but selective pressure in the steady state is that they shouldn't be too deadly.

When a new strain of the flu broke out in 1918 it killed 10s of millions of people.  While it was still exploding in numbers there wasn't much pressure on it to be less deadly.  But when it had infected as many as it was going to in the initial two-part outbreak (interrupted by the summer) the strains that became most prevalent going forward were much less deadly.  The descendants of that great pandemic are preying on us still as H1N1 flu but it normally isn't any deadlier than any other flu pandemic.  Sometimes there's some mutation that makes it both more virulent and more transmissible and we have a worse flu year but in general we've found a good equilibrium.  But when H1N1 jumped to pigs for a while and then jumped back to humans as the swine flu public health officials were understandably a bit freaked out.

What sorts of things cause less virulence?  Well, in 8 patients in Singapore we saw a mutation in SARS-2 that seem to have made the disease less dangerous but also better at hiding from the human immune system for longer.  And something similar happened with the some parts original SARS too.  Right now the virus is spreading rapidly and any strain that spreads less rapidly to live longer won't be anything but a tiny part of the current pandemic.  But as in 1918 after the pandemic finishes, however that happens, we should expect that the surviving strains of the disease will tend to be less deadly.

And I think this pandemic will end.  There have been reports of people getting re-infected with Covid-19 but no more than you'd expect form imperfect testing.   We even already have a couple of coronavirus vaccines.  It's been too expensive to develop a vaccine to human standards for something that causes a small fraction of common colds but immunologists were able to throw together a couple of vaccines for the common strains of coronavirus that affect dogs and cats respectively.  The dog one works great but immunity fades out over a year or two just like it does from a natural coronavirus infection so to retain immunity a dog needs periodic boosters.  The vaccine for cats sort of worked but not great.  That, I suppose, is an indication of why it takes so much effort to create a vaccine that works reliably in humans with no side effects.  There are indications that immunity to the original SARS and also MERS last longer and it would be nice if the SARS Covid 2 vaccine also lasted many years but I think having to get a yearly booster with your vaccine to this year's flu.

We'll vaccinate the rich world eventually, hopefully before we all get it.  But I expect it'll remain endemic for a long time.  But it should also decrease in danger over time as well.  Maybe not in one year or two but it will happen if it sticks around.  In 2030 what we'll have to worry about is that some new disease will cross over from a different species.  A new disease that hasn't had a chance to reach an equilibrium with us yet. 

Saturday, January 4, 2020

Read in 2019

2019 is dead, may it rest in peace.  One thing I hope to take from the year, though, is all the things I learned in the books I finished that year.   I'm not going to review them all, there are too many, but I'll break them down into categories and bold the ones I particularly liked.  Within a category there're in chronological order, except when I mixed them up when reshuffling categories but it should be mostly right.  Some books are hard to categorize, for instance is a history of DARPA science or technology?  So it's a bit arbitrary but hopefully useful.

Science

  • The Ends of the World: Supervolcanoes, Lethal Oceans, and the Search for Past Apocalypses by Peter Brannen
  • The 10,000 Year Explosion: How Civilization Accelerated Human Evolution by Gregory Cochran
  • Power, Sex, Suicide: Mitochondria and the Meaning of Life (reread) by Nick Lane
  • The Book of Why: The New Science of Cause and Effect by Judea Pearl and Dana Mackenzie 
  • Lost in Math: How Beauty Leads Physics Astray by Sabine Hossenfelder
  • What We Know about Climate Change by Kerry Emanuel


Technology

  • The Pentagon's Brain: An Uncensored History of DARPA, America's Top-Secret Military Research Agency by Annie Jacobsen
  • The History of the Future: Oculus, Facebook, and the Revolution That Swept Virtual Reality by Blake J Harris
  • How We Got to Now: Six Innovations That Made the Modern World by Steven Johnson
  • The Second Machine Age: Work, Progress, and Prosperity in a Time of Brilliant Technologies by Eric Brynjolfsson
  • One Giant Leap: The Impossible Mission That Flew Us to the Moon by Charles Fishman
  • Feeding Everyone No Matter What: Managing Food Security After Global Catastrophe by David Dekenberger
  • Clean Meat: How Growing Meat Without Animals Will Revolutionize Dinner and the World by Paul Shapiro
  • Loonshots: How to Nurture the Crazy Ideas That Win Wars, Cure Diseases, and Transform Industries by Safi Bahcall
  • The Value of the Moon: How to Explore, Live, and Prosper in Space Using the Moon's Resources by Paul D. Spudis


History

  • 1491: New Revelations of the Americas Before Columbus by Charles C. Mann
  • The Pursuit of Power by William Hardy McNeill
  • Bury the Chains by Adam Horschild
  • Benjamin Franklin: An American Life by WaltBenjamin Franklin: An American Lifeer Isaacson
  • Blitzed: Drugs in the Third Reich by Norman Ohler
  • Grand Expectations: The United States, 1945-1974 by James T Peterson
  • The Horse, the Wheel, and Language: How Bronze-Age Riders from the Eurasian Steppes Shaped the Modern World by David W. Anthony
  • 1177 B.C.: The Year Civilization Collapsed by Eric H Cline
  • The Pursuit of Power: Europe 1815-1914 by Richard J Evans
  • Hidden Figures by Margot Lee Shetterly
  • The House of Government: A Saga of the Russian Revolution by Yuri Slezkine
  • Titan: The Life of John D. Rockefeller, Sr. by Ron Chernow
  • Days of Rage: America's Radical Underground, the FBI, and the Forgotten Age of Revolutionary Violence by Bryan Burrough
  • The Anarchy: The East India Company, Corporate Violence, and the Pillage of an Empire by William Dalrymple
  • Energy: A Human History by Richard Rhodes
  • The Great Successor: The Divinely Perfect Destiny of Brilliant Comrade Kim Jong Un by Fifield, Anna 


Development Economics

  • The Next Factory of the World: How Chinese Investment Is Reshaping Africa by Irene Yuan Sun
  • Poor Economics: A Radical Rethinking of the Way to Fight Global Poverty by Abhijit V. Banerjee
  • Escape from Rome: The Failure of Empire and the Road to Prosperity by Walter Shiedel
  • How Asia Works: Success and Failure in the World's Most Dynamic Region by Joe Studwell
  • The Bottom Billion: Why the Poorest Countries Are Failing and What Can Be Done About It by Paul Collier


Fiction

  • Lies Sleeping by Ben Aaronovich
  • The Labrynth Index by Charles Stross
  • River of Gods by Ian McDonald
  • Blood Music by Greg Bear
  • Ascendancies: The Best of Bruce Sterling by Bruce Sterling
  • The Shadow of the Torturer by Gene Wolfe
  • Revenger by Alistair Reynolds
  • The Claw of the Conciliator by Gene Wolfe
  • The January Dancer (reread) by Michael Flynn
  • The Sword of the Lictor by Gene Wolfe
  • The Citadel of the Autarch by Gene Wolfe
  • Nation by Terry Pratchett
  • Exhalation: Stories by Ted Chiang
  • Dragon (reread) by Steven Brust
  • The Iron Dragon's Mother by Michael Swanwick
  • Downbelow Station by CJ Cherryh
  • Delta-V by Daniel Suarez
  • October Man by Ben Aaronovich
  • The White Queen by Phillipa Gregory
  • Royal Flash by George MacDonald Fraser
  • We Are Legion by Dennis E. Taylor
  • This Is How You Lose the Time War by Amal El-Motar and Max Gladstone 
  • The Best of Michael Swanwick by Michael Swanwick
  • Mission of Honor by David Webber


Misc

  • Intuition Pumps And Other Tools for Thinking by Daniel Dennet
  • The High Cost of Free Parking by Donald C Shoup
  • Age of Ambition: Chasing Fortune, Truth, and Faith in the New China by Evan Osnos
  • Democracy for Realists: Why Elections Do Not Produce Responsive Government by Christopher H. Achen and Larry M. Bartels
  • Bombing to Win: Air Power and Coercion in War by Robert A. Pape
  • Birth of a Theorem: A Mathematical Adventure by Cedric Villani
  • How To: Absurd Scientific Advice for Common Real-World Problems by Randall Monroe
  • Masters of Doom: How Two Guys Created an Empire and Transformed Pop Culture by David Kushner
  • Open Borders: The Science and Ethics of Immigration by Bryan Caplan
  • Eating the Dinosaur by Chuck Klosterman

Wednesday, January 1, 2020

Overlooked Jovian moons

It’s sad that books, TV shows, etc always overlook Callisto when talking about people having settlements on Jovian moons.  Basically nobody puts one on Io except as a weird research station which is great, because Io is objectively a terrible place to have to be unless you want to learn more about how hot sulfur behaves in high radiation environments.
Europa is a common one and there are reasons for that.  We can be sure it has a liquid ocean under all that ice, which means there’s a possibility of life.  If you want a colony in a Moon’s ocean that’s an ok place to put it but we think that Ganymede and Callisto also probably have oceans too.  And they have stuff that, like, isn’t water on their surfaces if you want access to other elements for some strange reason.  If you’re not going to put a colony underwater then Europa’s surface is super radioactive and unprotected humans will tend to get a lethal dose after one day on the surface, though under a kilometer of ice you’re fine
Ganymede has lots to recommend it, lots of ice *and* non-ice.  But its radiation is still bad.  Not immediately but you’ll get a yearly dose on the surface 30 times higher than the lowest dose clearly linked to cancer and 60 times higher than the one we let nuclear power plant operators be exposed to.  Enough shielding is very doable, particularly with all that ice around, but you’ll need to spend lots of time indoors.
But Callisto?  On Callisto you get the same dose of background radiation you get within Earth’s protective Van Allen belt.  There are some extra cosmic rays compared to down here in the atmosphere but it’s the same radiation environment the astronauts on the ISS see which seems to be basically fine.  Plus you get the same access to both ice and non-ice you get on Ganymede.  Clearly Callisto is where you make your first space settlement.
Oh, and there are a bunch of other moons but they’re tiny and don’t have enough gravity to make things like cooking or pooping convenient.  We don’t really know how healthy the 1/8 g on the big moons is compared to 0g or 1g so that might make a big health difference too.  Or not, there’s some research on the ISS going on now with animals in centrifuges that might give us a clue in a little while.

We're trying to make our SARS-2 tests better than we should

Ok, that's a somewhat provocative title but I think it's basically accurate.  During this pandemic the US in particular has had a pr...