Timing the SARS-CoV-2 Index Case in Hubei Province

Understanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province. By characterizing the likely dynamics of the virus before it was discovered, we show that over two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.

WH01 in 3.7% of samples. Again, there was little support for a root position on branches corresponding to the T28114C (2.5%) or C8782T (0.4%) mutations.
Time to stable coalescence in simulations . Across the simulated epidemics, a stable coalescence (i.e., non-shifting tMRCA from that point in time until the end of the simulated epidemic) was established after a median of 16 days after the index case was first infected; 95% of simulations reached a stable coalescence by day 53 post-index case infection (Fig.  S10A), indicating that the 100-day simulations were sufficient to determine time to stable coalescence. Importantly, the time at which stable coalescence was achieved represents when the tMRCA of the currently circulating lineages is within one day of the tMRCA of the lineages remaining at the end of the simulation . This point in time is when basal lineages ceased to be lost in the coalescent tree, not the tMRCA of the remaining viral lineages (Fig. S10B). At the time a stable coalescence was reached, a median of 16 people had been infected; 95% of simulations reached this stable coalescence after 1194 people had become infected. Recall that the empirical phylogenetic analysis from the Chinese epidemic appears to have reached a stable coalescence by 01 January 2020, when around 1000 people are believed to have been infected ( 22 ) .
Number of hospitalized individuals through time . There has also been speculation that hospitals in Hubei province were inundated with COVID-19 patients in October and November 2019 ( 36 ) . However, our primary simulation analysis conditioning on the first case being identified by 17 November 2019 suggests that an increase in hospitalizations due to COVID-19 would not have been notable until mid-to late-December. We note that our estimate of 0 to 36 hospitalizations as of 01 January 2020 in the primary analysis is less than the 42 hospitalizations that had been previously reported ( 7 ) . However, this value is contained within the 95% HPD of many robustness analyses (Fig. S8). Further, it is important to acknowledge that our model is based on parameters from Hao et al. during the period between 01 January and 22 January 2020, which occurred after SARS-CoV-2 was discovered and while there was still limited understanding of  . Therefore, we have little confidence in the precision of our estimates regarding the number of hospitalized patients in late-2019. Nonetheless, even across the various robustness analyses we explored, we never observed a substantial number of hospitalized patients in November 2019, even in the 99% extreme of our estimates (Fig. S8).

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. CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted November 24, 2020. ;https://doi.org/10.1101https://doi.org/10. /2020  28 . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted November 24, 2020. ; https://doi.org/10.1101/2020.11.20.392126 doi: bioRxiv preprint Fig. S5. Illustration of the interplay rejection sampling scheme and the SAPHIRE compartmental model. The top two examples would be accepted by both I/A and I-only rejection sampling, because the first ascertained (I) case came before the minimum date for the earliest case In contrast, the middle example would only be accepted by I/A sampling, because the first unascertained (A) case came before the minimum date for the earliest case, but the first ascertained (I) case did not. The bottom two examples would be always be rejected, because both the first ascertained and unascertained cases came after the minimum date for the earliest case Note that coalescence can happen any time after the index case is first infected, and there is no requirement for coalescence to occur after the first ascertained and unascertained individuals. The index case begins in the exposed (E) compartment and can be the individual that first transitions into the A or I compartments; though other subsequently infected individuals can progress to the A or I compartments before index case.

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. CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted November 24, 2020. ; Fig. S7 . Robustness analysis for the number of people infected SARS-CoV-2 based on the SAPHIRE model in late 2019. Innermost shading is 50% HPD, middle shading is 95% HPD, and outer shading is 99% HPD. Dates indicates the minimum bound for rejection sampling (Nov 17 or Dec 01). Clock indicates whether the tMRCA was inferred using a strict or relaxed (ULD) clock. Disease denotes which stage of infection in the SAPHIRE model (IA, Ascertained or Unascertained; or I, Ascertained only) must have been reached by the given date for rejection sampling. Innermost shading is 50% HPD, middle shading is 95% HPD, and outer shading is 99% HPD. Dates indicates the minimum bound for rejection sampling (Nov 17 or Dec 01). Clock indicates whether the tMRCA was inferred using a strict or relaxed (ULD) clock. Disease denotes which stage of infection in the SAPHIRE model (IA, Ascertained or Unascertained; or I, Ascertained only) must have been reached by the given date for rejection sampling.

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