Comment by tripletao | Hacker News Reader

Comment by tripletao | Hacker News Reader

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Note that the zoonotic path of Ebola into humans isn't well-understood. There was pretty good evidence of the path for SARS-1 though, and very good evidence for MERS. For SARS-CoV-2, there's still nothing, despite the recent emergence and considerably greater effort searching.

The "two lineages" argument has been grossly distorted by Worobey and the media. They're just two single-nucleotide polymorphisms apart, so they could easily have arisen in a single human-to-human transmission. SARS-CoV-2 averages something around a third of an SNP per human-to-human transmission, so ~10% of such transmissions differ by two SNPs.

If a missing link does exist, then it's just a single mutation away from either strain. So there's no reason to consider the "two lineages" too significant in any direction, unless you believe sampling in humans has been perfectly good. That belief seems unreasonable to me, especially since belief in a natural zoonotic origin requires us to believe sampling in animals has been perfectly bad.

https://mobile.twitter.com/jbloom_lab/status/153463060722071...

> They're just two single-nucleotide polymorphisms apart

The problem with that argument, is that it doesn't explain the polytomies and is misleading, as you accuse Worobey of being.

"Just a few SNPs" is disingenuous and glosses over the usefulness of this evidence that almost everyone agrees on - eg, that it's highly unlikely that lineage B evolved from lineage A. (Even Jesse Bloom agrees on this.)

It may take a bit to find consensus on the dual-zoonosis theory and related phylogenetics, but the eagerness with which people dismiss this issue drives me nuts.

https://twitter.com/jepekar/status/1499840349807656960

You're correct that it's highly unlikely that B evolved from A, but why do you think that's significant? We know the spread of SARS-CoV-2 is highly stochastic, with most lineages dying out and a few exploding, and we know the IFR in humans is small enough that considerable cryptic spread is possible before enough people die to raise the alarm.

So why do you take the two lineages as conclusive evidence of two zoonotic events (as Worobey has repeatedly claimed in the media, even though his papers are more cautious)? Given the above, I don't see how we can exclude that the two lineages evolved in early human cryptic spread, before we started sampling enough to draw a perfect phylogenetic tree.

I don't take two lineages to be conclusive evidence of multiple zoonotic events. However, the multiple polytomies for each are not easy to explain away.

Have you read Pekar's most recent paper in Science? I raise this in earnest, I'm reading it now. A lot of it follows the preprint, but the update more directly addresses many of the points we're discussing.

https://www.science.org/doi/10.1126/science.abp8337

My problem with the "just a couple mutations" deniers is that that viewpoint doesn't speak to any of the real phylogenic questions here.

I led with "just two mutations" because as far as I can tell, all of Worobey's or Pekar's reasoning starts from the assumption that there was no significant cryptic (unsampled) human spread. If the two lineages were tens of SNPs apart, then I believe that would be a reasonable assumption--it would be hard to explain how the virus could spread in humans long enough to accumulate that many mutations without causing enough sickness and mortality for someone to notice.

But with just two SNPs, I believe that assumption is invalid. So while I believe those authors have correctly observed that we're missing part of the evolutionary history of SARS-CoV-2, I don't see how they decided whether that's unsampled spread in animals vs. unsampled spread in humans, except under that incorrect assumption.

I hadn't read the final paper, but I'm looking at it now. I don't see any new points that don't depend on that assumption yet, though. Do you?

> all of Worobey's or Pekar's reasoning starts from the assumption that there was no significant cryptic (unsampled) human spread.

They don't assume that. See the discussion in Pekar. ("The high extinction rate [...] Failed introductions of intermediate haplotypes are also possible.") The whole point of their epidemiological modeling is to disentangle the likelihood of this happening. (See: "Separate introductions of lineages A and B")

The tMRCA doesn't allow enough time for any deep cryptic spread. The authors show this. It's not assumed.

> We show that it is highly unlikely that SARS-CoV-2 circulated widely in humans earlier than November 2019 and that there was limited cryptic spread, with, at most, dozens of SARS-CoV-2 infections in the weeks leading up to the inferred tMRCA, but likely far fewer.

The details of that epidemiological model start around page 7 of

https://www.science.org/doi/suppl/10.1126/science.abp8337/su...

I haven't fully studied all the layers yet, but as far as I can tell it's numerical sludge, in the same general direction as econometrics, with so many free parameters or arbitrary choices in the model that you could plausibly get almost any result you wanted. Similar models got their chance to make falsifiable predictions of the case count in the actual pandemic, and they failed repeatedly, often by huge margins, in both directions.

For a specific criticism, the authors report that they're robust against variation in doubling time, but nothing about robustness to the extent of the overdispersion of SARS-CoV-2's spread (i.e., the superspreader characteristic, where most patients infect very few people but a minority infect a lot). They appear to model that only through the connectivity of the infection network, which appears to be fixed. All other things being equal, more stochastic early spread will make it harder to confidently reach any conclusion.

I'm not saying this work isn't interesting at all, or that I could do better; but it's many layers of stacked uncertainty. I believe the confidence that the authors express in this paper is already excessive, and Worobey's statements to the media go considerably beyond that.

Numerical sludge. Got it.

Enjoy your criticism.

Sorry if that phrasing was too mean; I've described many models that I judged to be uselessly complex as "numerical sludge" in the past, including my own less successful efforts. Do you at least understand my specific objection above? You're almost certainly a better biologist than me, but differential equation models get a lot closer to my real expertise.

The output of their model is the structure of the resulting phylogenetic tree. I believe the primary determinant of that will be the extent of overdispersion of transmission, i.e. the shape of the pdf of how many people you expect each patient to infect. For example, let's say R0 = 2 and each patient always infects exactly two others. Then all lineages will survive (at least initially, until a significant fraction of the population is recovered and immune). The phylogenetic tree will be as perfect a binary tree as the mutation rate and our sampling permit. If we cut off the beginning, then we'll see many descendant lineages.

Instead, let's say the spread is absurdly overdetermined, so that each patient infects either zero others (with p = 0.99) or 200 (with p = 0.01). Then (after trying the simulation enough times for the pandemic to finally get started) our tree will just be a succession of super-spreading events, with far fewer lineages.

I believe that by manipulating that pdf, we can reshape that phylogenetic tree to almost anything we want. I see no description from the authors of why they believe the pdf resulting from their choice of a contact network is the right one, nor any study of robustness to changes in the shape of that pdf. Am I missing something?

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