Listeria monocytogenes (Stillbirths): Dose Response Models

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Listeria monocytogenes (Stillbirths in animals)

Author: Sushil Tamrakar


General overview of Listeria monocytogenes

Listeria monocytogenes is a food-borne pathogen responsible for the illness listeriosis. This disease is especially severe for susceptible people, including fetuses and immunocompromised individuals (Smith, Takeuchi et al. 2008).


http://www.cdc.gov/listeria/




Summary Data

Smith et al.(2008) studied dose-response model for Listeria monocytogenes induced stillbirths in nonhuman primates (Smith, Takeuchi et al. 2008) . Thirty-three pregnant rhesus monkeys (Macaca mulatta) were identified at 30 gestation days (gd) and L. monocytogenes was administered by nasogastric intubation. Animals were observed daily for changes in behavior or activity or signs of illness such as diarrhea. Similarly, Williams et al ( 2007 and 2009) explored fetal mortality in guinea pigs after oral exposure (Williams, Irvin et al. 2007; Williams, Castleman et al. 2009). Timed-pregnant guinea pigs were inoculated L. monocytogenes with whipping cream and the doses ranges from 104 CFU to 108 CFU. The animals were sacrificed on gestation day.


Experiment serial number Reference Host type Agent strain Route # of doses Dose units Response Best fit model Optimized parameter(s) LD50/ID50
289,290* [1][2] pooled oral 13 CFU stillbirths beta-Poisson α = 4.22E-02 , N50 = 1.78E+09 1.78E+09
289 [1] rhesus monkeys oral 8 CFU stillbirths beta-Poisson α = 4E-02 , N50 = 8.26E+08 8.26E+08
290 [2] guinea pig oral 5 CFU fetal mortality beta-Poisson α = 9.36E-02 , N50 = 4.67E+07 4.67E+07
*This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.


*Recommended Model

It is recommended that pooled model of experiment 289 and 290 pooled should be used as the best dose response model. More data means better fit.



Exponential and betapoisson model.jpg

Optimization Output for pooled data (experiment 289 and 290)

Rhesus monkey/Listeria monocytogenes
Dose Stillbirths Not stillbirths Total
316 0 1 1
1580 2 6 8
1E+04 0 4 4
2E+04 0 3 3
1E+05 2 9 11
126000 1 4 5
1E+06 2 7 9
1580000 2 4 6
1E+07 3 6 9
1.26E+07 2 3 5
1E+08 3 1 4
1.26E+08 2 2 4
3.98E+10 1 0 1


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 71.8 63.9 12 3.84
1.33e-15
21
1.49e-10
Beta Poisson 7.88 11 19.7
0.724
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.


Optimized parameters for the beta-Poisson model, from 500 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 4.22E-02 1.14E-02 1.54E-02 1.78E-02 1.26E-01 1.51E-01 2.71E-01
N50 1.78E+09 1.74E+06 4.42E+06 7.04E+06 2.28E+15 8.63E+16 8.36E+20


Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
beta Poisson model plot, with confidence bounds around optimized model




Optimization Output for experiment 289

Rhesus monkey/Listeria monocytogenes [1]
Dose Stillbirths Not stillbirths Total
316 0 1 1
1580 2 6 8
2E+04 0 3 3
126000 1 4 5
1580000 2 4 6
1.26E+07 2 3 5
1.26E+08 2 2 4
3.98E+10 1 0 1


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 51.4 47.7 7 3.84
4.95e-12
14.1
7.71e-09
Beta Poisson 3.68 6 12.6
0.72
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.
Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 4E-02 9.86E-04 9.94E-04 1.02E-02 1.22E-01 1.96E-01 3.05E-01
N50 8.26E+08 1.94E+03 4.54E+04 5.30E+05 8.90E+18 6.18E+22 4.86E+65



Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
beta Poisson model plot, with confidence bounds around optimized model



Optimization Output for experiment 290

Guinea pig/Listeria monocytogenes [2]
Dose Fetal mortality Not fetal mortality Total
1E+04 0 4 4
1E+05 2 9 11
1E+06 2 7 9
1E+07 3 6 9
1E+08 3 1 4


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 19.3 17.6 4 3.84
2.71e-05
9.49
0.000677
Beta Poisson 1.72 3 7.81
0.632
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.


Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 9.36E-02 1.19E-02 2.03E-02 2.95E-02 1.10E+00 1.02E+02 8.41E+02
N50 4.67E+07 9.56E+05 2.12E+06 3.23E+06 8.13E+11 4.28E+14 2.83E+23



Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
beta Poisson model plot, with confidence bounds around optimized model




References

  1. 1.0 1.1 1.2 Smith, M. A., K. Takeuchi, et al. (2008). "Dose-Response Model for Listeria monocytogenes-Induced Stillbirths in Nonhuman Primates." Infection and Immunity 76(2): 726-731
  2. 2.0 2.1 2.2 Williams, D., E. A. Irvin, et al. (2007)."Dose-Response of Listeria monocytogenes after Oral Exposure in Pregnant Guinea Pigs." Journal of Food Protection 70(5): 1122-1128


Williams D, Castleman J, et al. (2009) Risk of Fetal Mortality After Exposure to Listeria monocytogenes Based on Dose-Response Data from Pregnant Guinea Pigs and Primates. Risk Analysis 29(11): 1495-1505.