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> A typical molecular clock approach wouldn't give anywhere near the accuracy necessary to exclude evolution of lineage B (just two SNPs away) in humans You're

> A typical molecular clock approach wouldn't give anywhere near the accuracy necessary to exclude evolution of lineage B (just two SNPs away) in humans You're ignoring other data which is counter to the idea of B evolving from A in humans. Pekar's models are not the only evidence. - Early cases were predominantly B - A shows less generic divergence than B, this is what Pekar is talking about with regards to the discontinuity in the early clock. When we first started discussing this - I spoke up because I was annoyed by you trashing peer-reviewed papers when it was obvious you weren't even attempting to grok the phylogenetics involved. Still annoyed. It's been genuinely interesting watching the scientific debate to root the SC2 tree over the past few years because of the involved paradoxes. "Just a few SNPs" is just such a silly argument when stacked against peer-reviewed phylogenies in high-impact publications.

tripletao 4y ago
Have you looked at Pekar's full numerical stack yourself, as described in their supplemental materials? If yes, then why are you confident that their choice of the Barabasi-Albert algorithm to generate a fixed infection network correctly models the earliest spread of SARS-CoV-2 in humans? In particular, why choose to study robustness against doubling time (which seems intuitively like it wouldn't affect the shape of the tree much), but not robustness against that connectivity (which seems intuitively like it would)? The rest of their arguments depend fundamentally on the polytomy thing, because nothing else excludes an earlier (even September) first introduction into humans. With an earlier introduction and thus more extensive unsampled spread, it's much harder to insist that A and B would be first sampled in the same order in which they evolved in humans, or make any similar early claims with confidence. You are correct that I hadn't fully understood their polytomy argument before you brought it up, and I appreciate you bringing it to my attention. I still don't think it's very good, though. I later found Erik van Nimwegen's criticisms, which roughly followed my own; so I don't think I'm taking a fringe position here. Indeed, I've never seen anyone citing or defending Pekar engage in any way with the numerical complexity of that model. It seems like anyone who's looked inside the box becomes a critic, thus my hope that you'll do so. High-impact publications have shown unfortunate willingness to publish low-quality work that would exclude research-related origin of SARS-CoV-2. For example, I assume you followed Nature's publication, editor's note, and ultimate extensive correction of their pangolin paper, and that you agree pangolins aren't the proximal host. This makes me less inclined to trust in their reviewers here, and more inclined to trust my own judgment (or that of the two Twitter threads I've linked elsewhere).
- oasisbob 4y ago
  Yes, I've reviewed the supplemental materials. > because nothing else excludes an earlier (even September) first introduction into humans. With an earlier introduction and thus more extensive unsampled spread, it's much harder to insist that A and B would be first sampled in the same order in which they evolved in humans The tMRCA clearly excludes an earlier introduction. Because the tMRCA is based on genetic diversity, you cannot calculate a tMRCA based on all the known samples, get a date, and then say "oh, geez- well, there was also wide cryptic spread before that." It just doesn't make sense. Pekar addresses this point directly. A race between the first A and the first B is a strawman. Rather, it's the predominance of lineage B over A in the early pandemic which is interesting. It would be unexpected for lineage B to dominate if A came first. Much of the modeling is to get a handle on how unlikely that situation would be. It shouldn't be surprising that the models don't support it as being likely. (But, that's not the only evidence.) If you're willing to actually think about and engage on the phylogeny - stop with the "just a few SNPs" nonsense, and ask yourself what you really think the early origins looked like. If it really was a single introduction - Was lineage A ancestral? Was B ancestral? A C/C ancestor? A T/T ancestor? All these have interesting problems being supported by the data. Finally, after reading some of your earlier comments, I'm realizing that you're conflating several techniques from Pekar's paper, eg: > Have you looked at Pekar's full model, as set out mostly in the supplementary materials? This isn't any standard molecular clock approach. It's a byzantine stack of plausible but somewhat arbitrary assumptions, ending in a simulated phylogenetic tree. His epi simulations are separate from the tree-building, with the possible exception of rooting, which he was using the output of the models to inform. Otherwise, the epi modeling which everyone is hand wringing over is really separate and doesn't end "in a simulated phylogenetic tree." There /are/ novel methods used in the tree building (eg, non-reversibility of base substitutions), but that's a whole separate technique. > Essentially Pekar's argument is a "two introductions of the gaps"--that if their model of a single introduction doesn't conform to reality, then it must have been two introductions. BS. Again - understanding the paradoxes and debate involved in rooting the tree is basically required to understand the importance of this paper. The existing data is confounding and didn't conform to a logical understanding of viral evolution. A separate introduction elegantly explains the existing evidence. If their modeling isn't strong enough evidence for you, fine. But that's different than throwing everything out because you don't understand how "just a couple SNPs" can still provide sufficient resolution to make phylogenetic inferences possible. If you think that "just a couple SNPs" /don't/ provide enough for experts in the field to inform their phylogenies, at least get to that argument directly instead of throwing ignorant shade at an unrelated portion of the paper. Thanks for the links to those other threads. Nod's was interesting, but AFAICT, way off-base, starting around "Needless to say, early winter in Wuhan is not the Mardi Gras." Here's Pekar's earlier thread which I recently reread and found helpful for understanding the significance of the phylogeny (#20 is where he gets into how lineage A breaks the clock): https://twitter.com/jepekar/status/1499840335349911553 https://twitter.com/jepekar/status/1499840335349911553 and Worobey re-emphasizing that we're not just talking about a few SNPs, it's the shape of the tree which matters: https://twitter.com/michaelworobey/status/1570504674742239234 https://twitter.com/michaelworobey/status/157050467474223923...

tripletao 4y ago

Have you looked at Pekar's full numerical stack yourself, as described in their supplemental materials? If yes, then why are you confident that their choice of the Barabasi-Albert algorithm to generate a fixed infection network correctly models the earliest spread of SARS-CoV-2 in humans? In particular, why choose to study robustness against doubling time (which seems intuitively like it wouldn't affect the shape of the tree much), but not robustness against that connectivity (which seems intuitively like it would)? The rest of their arguments depend fundamentally on the polytomy thing, because nothing else excludes an earlier (even September) first introduction into humans. With an earlier introduction and thus more extensive unsampled spread, it's much harder to insist that A and B would be first sampled in the same order in which they evolved in humans, or make any similar early claims with confidence. You are correct that I hadn't fully understood their polytomy argument before you brought it up, and I appreciate you bringing it to my attention. I still don't think it's very good, though. I later found Erik van Nimwegen's criticisms, which roughly followed my own; so I don't think I'm taking a fringe position here. Indeed, I've never seen anyone citing or defending Pekar engage in any way with the numerical complexity of that model. It seems like anyone who's looked inside the box becomes a critic, thus my hope that you'll do so. High-impact publications have shown unfortunate willingness to publish low-quality work that would exclude research-related origin of SARS-CoV-2. For example, I assume you followed Nature's publication, editor's note, and ultimate extensive correction of their pangolin paper, and that you agree pangolins aren't the proximal host. This makes me less inclined to trust in their reviewers here, and more inclined to trust my own judgment (or that of the two Twitter threads I've linked elsewhere).

oasisbob 4y ago
Yes, I've reviewed the supplemental materials. > because nothing else excludes an earlier (even September) first introduction into humans. With an earlier introduction and thus more extensive unsampled spread, it's much harder to insist that A and B would be first sampled in the same order in which they evolved in humans The tMRCA clearly excludes an earlier introduction. Because the tMRCA is based on genetic diversity, you cannot calculate a tMRCA based on all the known samples, get a date, and then say "oh, geez- well, there was also wide cryptic spread before that." It just doesn't make sense. Pekar addresses this point directly. A race between the first A and the first B is a strawman. Rather, it's the predominance of lineage B over A in the early pandemic which is interesting. It would be unexpected for lineage B to dominate if A came first. Much of the modeling is to get a handle on how unlikely that situation would be. It shouldn't be surprising that the models don't support it as being likely. (But, that's not the only evidence.) If you're willing to actually think about and engage on the phylogeny - stop with the "just a few SNPs" nonsense, and ask yourself what you really think the early origins looked like. If it really was a single introduction - Was lineage A ancestral? Was B ancestral? A C/C ancestor? A T/T ancestor? All these have interesting problems being supported by the data. Finally, after reading some of your earlier comments, I'm realizing that you're conflating several techniques from Pekar's paper, eg: > Have you looked at Pekar's full model, as set out mostly in the supplementary materials? This isn't any standard molecular clock approach. It's a byzantine stack of plausible but somewhat arbitrary assumptions, ending in a simulated phylogenetic tree. His epi simulations are separate from the tree-building, with the possible exception of rooting, which he was using the output of the models to inform. Otherwise, the epi modeling which everyone is hand wringing over is really separate and doesn't end "in a simulated phylogenetic tree." There /are/ novel methods used in the tree building (eg, non-reversibility of base substitutions), but that's a whole separate technique. > Essentially Pekar's argument is a "two introductions of the gaps"--that if their model of a single introduction doesn't conform to reality, then it must have been two introductions. BS. Again - understanding the paradoxes and debate involved in rooting the tree is basically required to understand the importance of this paper. The existing data is confounding and didn't conform to a logical understanding of viral evolution. A separate introduction elegantly explains the existing evidence. If their modeling isn't strong enough evidence for you, fine. But that's different than throwing everything out because you don't understand how "just a couple SNPs" can still provide sufficient resolution to make phylogenetic inferences possible. If you think that "just a couple SNPs" /don't/ provide enough for experts in the field to inform their phylogenies, at least get to that argument directly instead of throwing ignorant shade at an unrelated portion of the paper. Thanks for the links to those other threads. Nod's was interesting, but AFAICT, way off-base, starting around "Needless to say, early winter in Wuhan is not the Mardi Gras." Here's Pekar's earlier thread which I recently reread and found helpful for understanding the significance of the phylogeny (#20 is where he gets into how lineage A breaks the clock): https://twitter.com/jepekar/status/1499840335349911553 https://twitter.com/jepekar/status/1499840335349911553 and Worobey re-emphasizing that we're not just talking about a few SNPs, it's the shape of the tree which matters: https://twitter.com/michaelworobey/status/1570504674742239234 https://twitter.com/michaelworobey/status/157050467474223923...