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Pathogen evolution in the emergence of infectious disease outbreaks

Infectious diseases that cannot transmit effectively between humans cannot cause sustained disease outbreaks. However, they can cause stuttering chains of transmission with several cases. These short human-to-human transmission chains provide opportunities for the pathogen to adapt to humans and enhance transmission potential. Therefore, even in cases where a pathogen initially introduced into a human population might have a reproduction number below 1, that is on average it is transmitted to less than one other person (bound to inevitably going extinct without pathogen evolution), if a pathogen mutates while infecting humans, its reproduction number might evolve to exceed 1, and emerge to cause sustained outbreaks.

This vignette explores the probability_emergence() function. This is based on the framework of Antia et al. (2003) which uses a multi-type branching process to calculate the probability that a subcritical zoonotic spillover will evolve into a more transmissible pathogen with a reproduction number greater than 1 and thus be able to cause a sustained epidemic from human-to-human transmission.

library(superspreading)
library(ggplot2)
library(scales)

We use probability_emergence() to replicate Figure 2b from Antia et al. (2003) showing how the probability of emergence changes for different wild-type reproduction numbers and different mutation rates. This assumes a 2-type branching process with a wild-type pathogen with \(R_0 < 1\) and a mutant pathogen with \(R_0 > 1\), we test with mutant reproduction numbers of 1.2, 1.5, 1,000.

R_wild <- seq(0, 1.2, by = 0.01)
R_mutant <- c(1.2, 1.5, 1000)
mutation_rate <- c(10^-1, 10^-3)

params <- expand.grid(
  R_wild = R_wild,
  R_mutant = R_mutant,
  mutation_rate = mutation_rate
)

prob_emerge <- apply(
  params,
  MARGIN = 1,
  FUN = function(x) {
    probability_emergence(
      R_wild = x[["R_wild"]],
      R_mutant = x[["R_mutant"]],
      mutation_rate = x[["mutation_rate"]],
      num_init_infect = 1
    )
  }
)
res <- cbind(params, prob_emerge = prob_emerge)
ggplot(data = res) +
  geom_line(
    mapping = aes(
      x = R_wild,
      y = prob_emerge,
      colour = as.factor(mutation_rate),
      linetype = as.factor(R_mutant)
    )
  ) +
  scale_y_continuous(
    name = "Probability of emergence",
    transform = "log",
    breaks = log_breaks(n = 6),
    limits = c(10^-5, 1)
  ) +
  scale_colour_manual(
    name = "Mutation rate",
    values = c("#228B22", "black")
  ) +
  scale_linetype_manual(
    name = "Mutant pathogen R0",
    values = c("dotted", "dashed", "solid")
  ) +
  scale_x_continuous(
    name = expression(R[0] ~ of ~ introduced ~ pathogen),
    limits = c(0, 1.2),
    n.breaks = 7
  ) +
  theme_bw()
#> Warning in scale_y_continuous(name = "Probability of emergence", transform =
#> "log", : log-2.718282 transformation introduced infinite values.

Line plot showing the probability of emergence of a pathogen as a function of the basic reproduction number (R0) of the introduced pathogen. The x-axis represents the R0 of the introduced pathogen, ranging from 0 to 1.2. The y-axis shows the probability of emergence on a logarithmic scale from 1e-05 to 1. Lines vary by mutation rate (green for 0.001 and black for 0.1) and by mutant pathogen R0 (dotted for R0 = 1.2, dashed for R0 = 1.5, solid for R0 = 1000). For both mutation rates, the probability of emergence increases with the R0 of the introduced pathogen and with the R0 of the mutant. Higher mutation rates and higher mutant R0s lead to higher probabilities of emergence.

Next we’ll replicate Figure 3a from Antia et al. (2003). This uses an extension of the 2-type (or one-step) branching process model to include multiple intermediate mutants/variants between the introduced wild-type and the fully-evolved pathogen with an \(R > 1\). In Antia et al. (2003) this is called the jackpot model. The introduced pathogen is subcritical (\(R < 1\)), and the intermediate variants have the same reproduction number as the wild-type. Only the final fully-evolved variant is supercritical (\(R > 1\)).

We use the same number of intermediate mutants between the wild-type and the fully-evolved strain as Antia et al. (2003).

R_wild <- seq(0, 1.2, by = 0.01)
R_mutant <- 1.5
mutation_rate <- c(10^-1)
num_mutants <- 0:4

params <- expand.grid(
  R_wild = R_wild,
  R_mutant = R_mutant,
  mutation_rate = mutation_rate,
  num_mutants = num_mutants
)

prob_emerge <- apply(
  params,
  MARGIN = 1,
  FUN = function(x) {
    probability_emergence(
      R_wild = x[["R_wild"]],
      R_mutant = c(rep(x[["R_wild"]], x[["num_mutants"]]), x[["R_mutant"]]),
      mutation_rate = x[["mutation_rate"]],
      num_init_infect = 1
    )
  }
)
res <- cbind(params, prob_emerge = prob_emerge)
ggplot(data = res) +
  geom_line(
    mapping = aes(
      x = R_wild,
      y = prob_emerge,
      colour = as.factor(num_mutants)
    )
  ) +
  scale_y_continuous(
    name = "Probability of emergence",
    transform = "log",
    breaks = log_breaks(n = 6),
    limits = c(10^-5, 1)
  ) +
  scale_colour_brewer(
    name = "Number of \nintermediate mutants",
    palette = "Set1"
  ) +
  scale_x_continuous(
    name = expression(R[0] ~ of ~ introduced ~ pathogen),
    limits = c(0, 1.2),
    n.breaks = 7
  ) +
  theme_bw()
#> Warning in scale_y_continuous(name = "Probability of emergence", transform =
#> "log", : log-2.718282 transformation introduced infinite values.

Line plot showing the probability of emergence of a pathogen as a function of the basic reproduction number (R0) of the introduced pathogen, with varying numbers of intermediate mutants before reaching the fully-evolved mutant. The x-axis represents the R0 of the introduced pathogen (ranging from 0 to 1.2), and the y-axis shows the probability of emergence on a logarithmic scale from 1e-05 to 1. Lines represent different numbers of intermediate mutants: red for 0, blue for 1, green for 2, purple for 3, and orange for 4. As the number of required intermediate mutants increases, the probability of emergence decreases across all R0 values. All curves rise with increasing R0, and converge at higher R0 values near 1.2.

Thus far we’ve only introduced a single infection, however, just as with probability_epidemic() and probability_extinct(), we extend the method of Antia et al. (2003) and introduce multiple initial human infections using the num_init_infect argument.

R_wild <- seq(0, 1.2, by = 0.01)
R_mutant <- 1.5
mutation_rate <- 10^-1
num_mutants <- 1
num_init_infect <- seq(1, 9, by = 2)

params <- expand.grid(
  R_wild = R_wild,
  R_mutant = R_mutant,
  mutation_rate = mutation_rate,
  num_mutants = num_mutants,
  num_init_infect = num_init_infect
)

prob_emerge <- apply(
  params,
  MARGIN = 1,
  FUN = function(x) {
    probability_emergence(
      R_wild = x[["R_wild"]],
      R_mutant = c(rep(x[["R_wild"]], x[["num_mutants"]]), x[["R_mutant"]]),
      mutation_rate = x[["mutation_rate"]],
      num_init_infect = x[["num_init_infect"]]
    )
  }
)
res <- cbind(params, prob_emerge = prob_emerge)
ggplot(data = res) +
  geom_line(
    mapping = aes(
      x = R_wild,
      y = prob_emerge,
      colour = as.factor(num_init_infect)
    )
  ) +
  scale_y_continuous(
    name = "Probability of emergence",
    transform = "log",
    breaks = log_breaks(n = 6),
    limits = c(10^-5, 1)
  ) +
  scale_colour_brewer(
    name = "Number of introductions",
    palette = "Set1"
  ) +
  scale_x_continuous(
    name = expression(R[0] ~ of ~ introduced ~ pathogen),
    limits = c(0, 1.2),
    n.breaks = 7
  ) +
  theme_bw()
#> Warning in scale_y_continuous(name = "Probability of emergence", transform =
#> "log", : log-2.718282 transformation introduced infinite values.

Line graph showing the relationship between the basic reproduction number (R0) of an introduced pathogen and the probability of emergence, under varying numbers of introductions. The x-axis represents R0 values from 0 to 1.2, and the y-axis (logarithmic scale) represents the probability of emergence, from 1e-05 to 1. Five curves are shown for different numbers of introductions: 1 (red), 3 (blue), 5 (green), 7 (purple), and 9 (orange). All curves show increasing probability of emergence with higher R0, and higher numbers of introductions consistently increase emergence probability. Increasing the number of initial infections has diminishing increases on the probability of emergence with greater number of introductions.

Antia, Rustom, Roland R. Regoes, Jacob C. Koella, and Carl T. Bergstrom. 2003. “The Role of Evolution in the Emergence of Infectious Diseases.” Nature 426 (6967): 658–61. https://doi.org/10.1038/nature02104.

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