How About a Remote Variolation Study?

post by Liron · 2020-04-03T12:04:04.439Z · LW · GW · 24 comments

Robin in Variolation May Cut Covid19 Deaths 3-30x:

Just as replacing accidental smallpox infections with deliberate low dose infections cut smallpox deaths by a factor of 10 to 30, a factor of 3-30 is plausible for Covid19 death rate cuts due to replacing accidental Covid19 infections with deliberate small dose infections.
[...] Systematic variolation experiments involving at most a few thousand volunteers seem sufficient to get evidence not only on death rates, but also on ideal infection doses and methods, and on the value of complementary drugs that slow viral replication (e.g., remdesivir). [...] A small early trial could generate much useful attention and discussion regarding this strategy

Zvi in Taking Initial Viral Load Seriously [LW · GW]:

My prior at this point is that the difference between a low and high initial viral load of Covid-19 is large. [...] That difference is a really, really big deal. It’s a much bigger deal than getting enough ventilators. It’s potentially a bigger deal than having a medical system at all.
[...] The more I think about the Covid-19 situation, the more I think the highest leverage thing most people reading this can do is to find ways to get our hands on better data.

Right now we are all very keen to know the values of X and P in this statement:

"If you have an X% risk of infection with a large inoculum in the next month, you should deliberately infect yourself now with a small inoculum via protocol P"

The following are sufficient for many people to undertake variolation for themselves and their loved ones:

A. An easy variolation protocol

B. Proof that variolation works to reduce COVID hospitalization rate 3x+

What we're missing right now:

1. A few plausible ideas for variolation protocols

2. A study where 10k volunteers try the various protocols, then get tested for how large of an inoculum they got (data on the variolation protocols), then report their outcomes (data on variolation itself)

Does anyone have any ideas for #1?

For #2, a remote study on thousands of volunteer heroes self-variolating from within their current self-quarantines (isolated from all non-volunteers) seems like the fastest and cheapest way to get initial data.

This doesn't necessarily have to be a "Scientific" study. It can be a crowdsourced, crowdfunded movement. The data will be lower quality than scientific-study data, but higher quantity. We could plausibly get 100k volunteers' worth of data on variolation protocol design and variolation effectiveness.

How about a remote variolation study?


Comments sorted by top scores.

comment by cousin_it · 2020-04-04T13:38:20.848Z · LW(p) · GW(p)
  1. Spain has stabilized at 7K new cases/day, Italy at 5K new cases/day. At this rate it will take many months to reach a significant percentage of the population. The same will probably happen in the US. Most people won't get infected, so trying amateur vaccination is more dangerous than doing nothing.

  2. How will you send doses to volunteers? If I were a delivery company, I would refuse to deliver this and would call the cops.

  3. How will you measure the results? People have trouble measuring the death rate from corona, sometimes they can't even agree on the order of magnitude. It's really low and depends on demographic factors, environment, treatment and other things that aren't well understood. If you want to measure a change in that rate by looking at 10k remote volunteers in reasonable time, I'd like to see your methodology and error bounds.

Replies from: Liron
comment by Liron · 2020-04-04T16:16:24.556Z · LW(p) · GW(p)
  1. Claiming that infections will halt at a small fraction of the population may be fine for Plan A, but shouldn’t we prepare a Plan B for the case where this claim is false?

  2. Maybe the variolation protocol can include instructions for how someone in your area with COVID can donate e.g. a tube of water mixed with their cough and how to get a small part of that into your rectum or whatever... I know it sounds crazy but proving out a potential 30x CFR reduction is a BIG DEAL

  3. It seems easy enough to at least just have participants report whether or not they ever required hospitalization.

Replies from: cousin_it
comment by cousin_it · 2020-04-04T17:35:13.279Z · LW(p) · GW(p)

Let's say X% get hospitalized within 2 weeks. What's the highest value of X that would say variolation is a good idea? Keep in mind that:

  • The demographics of your sample aren't the same as the general population, hopefully you didn't include many 60+ folks.

  • You don't know how many botched the protocol. Could botch in any direction (dose too high, too low, or no dose at all).

  • You don't know the hospitalization rate after contacting corona in normal ways, which can also be low dose. Many people don't get tested now and the epidemic is spreading.

  • Etc.

Replies from: Liron
comment by Liron · 2020-04-04T18:46:49.564Z · LW(p) · GW(p)
Let's say X% get hospitalized within 2 weeks. What's the highest value of X that would say variolation is a good idea?

Roughly X <= 1%. Something like 1/10 to 1/30 of the average 2-week hospitalization rate for a similar data set of non-study people is the success case. Assuming that the total study size has a sample of 10k+ participants, it's not that hard to get a strong signal of success out of the data.

What's special about this situation, besides the desperate emergency, is that the effect size we're hoping to detect here is nothing short of huge.

You don't know how many botched the protocol.

If video documentation of the full protocol is required to count someone in the study, the protocol accuracy could probably get within a 2x factor of having a professional administering it in meatspace.

You don't know the hospitalization rate after contacting corona in normal ways, which can also be low dose. Many people don't get tested now and the epidemic is spreading.

Aren't we confident that the hospitalization rate from getting it normal ways is 2-20%, and isn't that enough to go on?

Replies from: cousin_it
comment by cousin_it · 2020-04-05T16:34:10.580Z · LW(p) · GW(p)

Yes, if the potential effect size is large, you can get away with imprecise answers to some questions. But if there are many questions, at some point your "imprecision budget" will be spent. For example, will you be able to detect if your dosing leads to later hospitalization instead of no hospitalization? Or it weakens immunity instead of strengthening it?

Replies from: Liron
comment by Liron · 2020-04-06T00:52:32.450Z · LW(p) · GW(p)

I'm pretty optimistic that we have enough imprecision budget to work with if we put our heads together. Unfortunately, this comment section hasn't been very lively so far.

comment by Liron · 2020-04-03T18:00:04.315Z · LW(p) · GW(p)

Does anyone have an estimate of how effective convalescent serum is in giving the recipient immunity?

comment by leggi · 2020-04-03T13:06:34.530Z · LW(p) · GW(p)

"deliberate low dose infections" is a method of VACCINATION. ( or could be referred to as inoculation)

The usage of the term "variolation" is not correct. Variolation is specific to smallpox.

Replies from: ChristianKl
comment by ChristianKl · 2020-04-03T15:19:12.064Z · LW(p) · GW(p)

Language use is not either correct or incorrect. Good language use helps the reader to understand what's meant and how the entity that's named relates to other entities.

While this usage of the word "variolation" doesn't seem to be standard usage, I don't see how it's a naming choice with bad consequences. No reader is going to assume that we want to give people smallpox when we talk about it with those terms.

The terms "vaccination" and "inoculation" seem to me very broad for this case.

Do you have a more concrete argument why another term would be benefitial to use here?

Replies from: leggi
comment by leggi · 2020-04-03T19:21:47.797Z · LW(p) · GW(p)
Language use is not either correct or incorrect.

When it comes to medical issues language can be correct or incorrect. It matters.

If I went into hospital to have a debridement and someone decided amputation was an alternative I'd be pretty pissed waking up to find something had been chopped off rather than cleaned up.

It's not a matter of using variolation having a "standard usage" - it has a specific meaning. I don't think anyone will assume you want to give someone smallpox, but it does reduce the credibility of what is being said when variolation is the term chosen. (edited to add: variolation from variola = smallpox).

This website is called lesswrong, here's an opportunity to be a lot less wrong about something.

I'm not here to make friends, or get praise, or karma points and I will continue to point out errors made by people who are dabbling in subjects that they have little/no prior knowledge of.

Either people will consider what I've said and do some research for themselves. Or not.

Replies from: polytope, ChristianKl
comment by polytope · 2020-04-04T20:47:05.453Z · LW(p) · GW(p)

Couldn't you have also made the exact same argument for the word "vaccination" some number of generations ago, for almost exactly the same reason? It too derives from root words about a practice intended for protecting specifically against smallpox. (Namely, infecting someone with cowpox).

When words are so overly specific so as to almost completely fall out of usefulness for their original meaning (as in the case of both vaccination and variolation, since smallpox is not in circulation any more), it seems pretty natural to see people to repurpose them for other closely-related or more general meanings - that's certainly one common way language evolves.

If the original meaning is no longer even remotely relevant (so misunderstanding is vanishingly unlikely) and the new meaning is a natural-to-infer and useful extension for the topic being discussed, then this seems like good communication, which is what words are for.

Replies from: leggi
comment by leggi · 2020-04-04T18:26:39.975Z · LW(p) · GW(p)

No it doesn't seem "pretty natural to see people re-purpose" variolation for something that would be labelled in standard and accepted medical terms as vaccination with a live virus.

Find some people in the medical profession that think it's a good idea then I may reconsider my stance, otherwise I've made my point and don't intend to post any more comments on the subject.

comment by ChristianKl · 2020-04-05T14:35:10.070Z · LW(p) · GW(p)
This website is called lesswrong, here's an opportunity to be a lot less wrong about something.

Wrong in the sense of the sequences doesn't mean Inconsistent with how authorities define a term or Not in line with the platonic form towards which a word points. It's rather about having a map of the world that makes wrong empiric predictions.

comment by ChristianKl · 2020-04-03T15:12:49.013Z · LW(p) · GW(p)

Basically you propose to do large scale medical experimention with humans without asking any ethics board where people can potentially die because they receive a dangerous medical intervention.

While I do like the spirit, this isn't the time for it. This is likely highly illegal in most jurisdiction and there's danger of government being angry, charging people with manslaughter and practicing medicine without license. Maybe you even violate some bioterrorism laws. There the potential for collateral damage if you would organize it on a website like ours.

Replies from: Benquo, Kenny
comment by Benquo · 2020-04-03T15:46:52.871Z · LW(p) · GW(p)

A crisis with massive blatant institutional failure seems like exactly the time for courage and the willingness to do things that might get one in trouble, if they're the right thing to do.

comment by Kenny · 2020-04-04T07:35:00.635Z · LW(p) · GW(p)

The reason not to do something like this is because it wouldn't work, not because it's not approved by an official "ethics board".

Informing volunteers would be relatively easy and I definitely don't think the post author was proposing not informing participants of the risks.

I do agree that this should be its own project, separate from this site.

I also don't think this would likely produce good-enough data. I'm not confident that enough participants could be found, and verified, as having followed any protocol that could be designed (e.g. provide sufficient evidence of them being infected and at a low dose).

Replies from: Liron, ChristianKl
comment by Liron · 2020-04-04T16:10:15.984Z · LW(p) · GW(p)

What if all participants have to post a video of themselves taking a test that shows that they’re negative for COVID, and then of performing the variolation protocol?

Replies from: ChristianKl, Kenny
comment by ChristianKl · 2020-04-05T21:04:50.700Z · LW(p) · GW(p)

Good tests will test positive a few days after a person gets infected and also take time to verify that the person has the virus.

Where I'm living in Germany people are also joking that the easiest way to get the virus might be to go get tested because that puts you into an envirioment where you are more likely to meet other patients.

Replies from: Liron
comment by Liron · 2020-04-06T00:54:24.619Z · LW(p) · GW(p)

A simple rule can be that anyone who has been self-quarantining for 14+ days can be considered negative at the start of the test. We wouldn't lose that much data quality with that rule IMO.

comment by Kenny · 2020-04-04T19:32:10.102Z · LW(p) · GW(p)

That's a good idea, but it doesn't seem like tests will be widespread anytime soon, and maybe not available to individuals for even longer (or ever).

But the video idea is good. And maybe it could be used for participants to rehearse both the testing and variolation protocols before performing them for real.

Replies from: Liron
comment by Liron · 2020-04-04T19:41:20.240Z · LW(p) · GW(p)

Yes the study could have everyone get ready to kick off as soon as tests are widely distributed. Or it can just use proxy tests like temperature, heart rate and oxygen saturation. The study has the luxury of potentially compromising accuracy on one or two major variables because it’s looking to detect a 3-30x effect.

comment by ChristianKl · 2020-04-05T21:00:30.060Z · LW(p) · GW(p)

The problem is not directly the ethics board disagreeing, but that you need institutional protection for otherwise an angry prosecutor who wants to do something to reduce the spread about the disease can easily throw you into prison.

Ethic board approval would be a way to build up protection against that kind of institutional attack.

I don't think your information video will prevent you from going to prison for manslaughter when someone in your study dies from it.

Replies from: Kenny, Liron
comment by Kenny · 2020-04-06T16:38:42.604Z · LW(p) · GW(p)

You are pointing out real costs to this idea and I don't disagree that what you describe are real risks.

But it seems extremely unlikely – effectively impossible – that anything like this would ever be approved by an "ethics board" so seeking approval would be a waste of resources.

Someone, or some group of people, being prosecuted or risking being prosecuted would potentially be a heroic sacrifice – not a flagrant mistake.

comment by Liron · 2020-04-06T00:55:35.322Z · LW(p) · GW(p)

The lead of the study can be in a country that is unlikely to prosecute, or anonymous.