3 ms·

Glad we're on the same page about the multiple techniques now. Statements you made like, "Pekar et al. do some complicated phylogenetic modeling that purports t

Glad we're on the same page about the multiple techniques now. Statements you made like, "Pekar et al. do some complicated phylogenetic modeling that purports to show the MRCA in humans is too recent" and "This isn't any standard molecular clock approach. It's a byzantine stack of plausible but somewhat arbitrary assumptions" made it clear there was confusion before. Their tree is based off a couple novel modification to established techniques. Your characterizations were inaccurate and laughable. > It carries a different set of plausible but arbitrary assumptions though, again about the stochasticity/overdispersion and sampling rate of early spread, just less directly. So, you don't only have problems with the modeling of the authors, but their base phylogeny too? Do you reject their tMRCA? Good grief. I'm still looking forward to discussing the molecular phylogenetics of this paper sometime.

tripletao 4y ago
On reflection, I believe the first of my statements that you've quoted was indeed incorrect, and that I was also incorrect when I just wrote: > Their former model [...] purports to independently establish tMRCA in humans too recent for significant cryptic spread. Even if SARS-CoV-2 really entered humans in December, with minimal cryptic spread, that's still enough time for the two lineages to evolve in humans, since they're (sorry) just two SNPs apart. I believe Worobey knows this, and that's the reason why he emphasizes the "Separate introductions" model, since their polytomy thing--and not any question of time for cryptic spread--is their best and only argument to exclude that. So I was wrong to mention the tMRCA at all, since even perfect knowledge of that wouldn't tell us confidently how the two lineages arose. The second of my statements seems correct to me. Not only is their argument for two introductions not a standard molecular clock approach, but it's not a molecular clock approach at all, since "Inferring" provides no support. Their only support comes from the polytomy thing in "Separate". This makes the accuracy of their epidemiological simulation highly relevant, thus the "hand-wringing" over that. I'd note that you yourself referred me to "Separate", back in: https://news.ycombinator.com/item?id=32258096 https://news.ycombinator.com/item?id=32258096 So why did you switch to "Inferring"? I guess we could discuss that too, but per above I don't believe that could provide significant support for two introductions into humans, and thus not for natural vs. research-related origin. Do you believe otherwise? Or do you just mean the approach is of general interest, independently of that question of origin?
- deleted 4y ago
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- oasisbob 4y ago
  > Even if SARS-CoV-2 really entered humans in December, with minimal cryptic spread, that's still enough time for the two lineages to evolve in humans, since they're (sorry) just two SNPs apart. This isn't the evidence the authors present. The argument isn't "there isn't enough time to go from A -> B." IIRC, I've seen similar acknowledgements that even more rare mutations have been observed in a single transmission during the course of the pandemic. They're just highly improbable. The most direct evidence (as I see it) for B not evolving from A in humans is the unexpected lack of genetic divergence in lineage A compared to B. Lineage B should show a younger molecular clock, it doesn't. > I believe Worobey knows this, and that's the reason why he emphasizes the "Separate introductions" model, since their polytomy thing--and not any question of time for cryptic spread--is their best and only argument to exclude that. So I was wrong to mention the tMRCA at all, since even perfect knowledge of that wouldn't tell us confidently how the two lineages arose. Nonsense. The tMRCA is key evidence in how the lineages arose. One of the reasons for the epi modeling was to figure out the plausible time between the primary case and index case. It shows there is at most a few dozen people infected before the genetic diversity was captured through sampling. (`Results: Minimal cryptic circulation of SARS`) I don't think you understand their argument here, at all. > Not only is their argument for two introductions not a standard molecular clock approach, but it's not a molecular clock approach at all, since "Inferring" provides no support > So why did you switch to "Inferring"? I don't understand why you're bristling and reading into the terminology here. https://plato.stanford.edu/entries/phylogenetic-inference/ https://plato.stanford.edu/entries/phylogenetic-inference/ Please elaborate why you think their use of the molecular clock is novel. It's really not. > Do you believe otherwise? Or do you just mean the approach is of general interest, independently of that question of origin? As explained above, I think the authors provide compelling evidence of multiple introductions using solid phylogenetic inference and solid molecular epidemiology. Bottom line is that there simply isn't an alternate hypothesis which explains the available evidence, and they illustrate why. Here's a video you might not have seen, with Pekar and Wertheim. I've cued up the portion with a great explanation of why the evidence in the MRCA and genomics is so important. If you're going to continue to try and tear down their arguments, you probably want to really get this part. https://www.youtube.com/watch?v=TYqJCdqdkio&t=3330 https://www.youtube.com/watch?v=TYqJCdqdkio&t=3330 (especially 1h12m45, and 1h19m)

tripletao 4y ago

On reflection, I believe the first of my statements that you've quoted was indeed incorrect, and that I was also incorrect when I just wrote: > Their former model [...] purports to independently establish tMRCA in humans too recent for significant cryptic spread. Even if SARS-CoV-2 really entered humans in December, with minimal cryptic spread, that's still enough time for the two lineages to evolve in humans, since they're (sorry) just two SNPs apart. I believe Worobey knows this, and that's the reason why he emphasizes the "Separate introductions" model, since their polytomy thing--and not any question of time for cryptic spread--is their best and only argument to exclude that. So I was wrong to mention the tMRCA at all, since even perfect knowledge of that wouldn't tell us confidently how the two lineages arose. The second of my statements seems correct to me. Not only is their argument for two introductions not a standard molecular clock approach, but it's not a molecular clock approach at all, since "Inferring" provides no support. Their only support comes from the polytomy thing in "Separate". This makes the accuracy of their epidemiological simulation highly relevant, thus the "hand-wringing" over that. I'd note that you yourself referred me to "Separate", back in: https://news.ycombinator.com/item?id=32258096 https://news.ycombinator.com/item?id=32258096 So why did you switch to "Inferring"? I guess we could discuss that too, but per above I don't believe that could provide significant support for two introductions into humans, and thus not for natural vs. research-related origin. Do you believe otherwise? Or do you just mean the approach is of general interest, independently of that question of origin?

deleted 4y ago
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oasisbob 4y ago
> Even if SARS-CoV-2 really entered humans in December, with minimal cryptic spread, that's still enough time for the two lineages to evolve in humans, since they're (sorry) just two SNPs apart. This isn't the evidence the authors present. The argument isn't "there isn't enough time to go from A -> B." IIRC, I've seen similar acknowledgements that even more rare mutations have been observed in a single transmission during the course of the pandemic. They're just highly improbable. The most direct evidence (as I see it) for B not evolving from A in humans is the unexpected lack of genetic divergence in lineage A compared to B. Lineage B should show a younger molecular clock, it doesn't. > I believe Worobey knows this, and that's the reason why he emphasizes the "Separate introductions" model, since their polytomy thing--and not any question of time for cryptic spread--is their best and only argument to exclude that. So I was wrong to mention the tMRCA at all, since even perfect knowledge of that wouldn't tell us confidently how the two lineages arose. Nonsense. The tMRCA is key evidence in how the lineages arose. One of the reasons for the epi modeling was to figure out the plausible time between the primary case and index case. It shows there is at most a few dozen people infected before the genetic diversity was captured through sampling. (`Results: Minimal cryptic circulation of SARS`) I don't think you understand their argument here, at all. > Not only is their argument for two introductions not a standard molecular clock approach, but it's not a molecular clock approach at all, since "Inferring" provides no support > So why did you switch to "Inferring"? I don't understand why you're bristling and reading into the terminology here. https://plato.stanford.edu/entries/phylogenetic-inference/ https://plato.stanford.edu/entries/phylogenetic-inference/ Please elaborate why you think their use of the molecular clock is novel. It's really not. > Do you believe otherwise? Or do you just mean the approach is of general interest, independently of that question of origin? As explained above, I think the authors provide compelling evidence of multiple introductions using solid phylogenetic inference and solid molecular epidemiology. Bottom line is that there simply isn't an alternate hypothesis which explains the available evidence, and they illustrate why. Here's a video you might not have seen, with Pekar and Wertheim. I've cued up the portion with a great explanation of why the evidence in the MRCA and genomics is so important. If you're going to continue to try and tear down their arguments, you probably want to really get this part. https://www.youtube.com/watch?v=TYqJCdqdkio&t=3330 https://www.youtube.com/watch?v=TYqJCdqdkio&t=3330 (especially 1h12m45, and 1h19m)