Listeria monocytogenes (Stillbirths in animals)
Author: Sushil Tamrakar
General overview of Listeria monocytogenes
Listeria monocytogenes is a foodborne 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 doseresponse model for Listeria monocytogenes induced stillbirths in nonhuman primates (Smith, Takeuchi et al. 2008) . Thirtythree 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). Timedpregnant guinea pigs were inoculated L. monocytogenes with whipping cream and the doses ranges from 10^{4} CFU to 10^{8} 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) 
LD_{50}/ID_{50}

289,290* 
^{[1]}^{[2]} 
pooled 

oral 
13 
CFU 
stillbirths 
betaPoisson 
α = 4.22E02 , N_{50} = 1.78E+09 
1.78E+09

289 
^{[1]} 
rhesus monkeys 

oral 
8 
CFU 
stillbirths 
betaPoisson 
α = 4E02 , N_{50} = 8.26E+08 
8.26E+08

290 
^{[2]} 
guinea pig 

oral 
5 
CFU 
fetal mortality 
betaPoisson 
α = 9.36E02 , N_{50} = 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.
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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

Exponential

71.8

63.9

12

3.84 1.33e15

21 1.49e10

Beta Poisson

7.88

11

19.7 0.724

BetaPoisson fits better than exponential; cannot reject good fit for betaPoisson.


Optimized parameters for the betaPoisson model, from 500 bootstrap iterations
Parameter

MLE estimate

Percentiles

0.5% 
2.5% 
5% 
95% 
97.5% 
99.5%

α

4.22E02

1.14E02 
1.54E02 
1.78E02 
1.26E01 
1.51E01 
2.71E01

N_{50}

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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

Exponential

51.4

47.7

7

3.84 4.95e12

14.1 7.71e09

Beta Poisson

3.68

6

12.6 0.72

BetaPoisson fits better than exponential; cannot reject good fit for betaPoisson.


Optimized parameters for the betaPoisson model, from 10000 bootstrap iterations
Parameter

MLE estimate

Percentiles

0.5% 
2.5% 
5% 
95% 
97.5% 
99.5%

α

4E02

9.86E04 
9.94E04 
1.02E02 
1.22E01 
1.96E01 
3.05E01

N_{50}

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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

Exponential

19.3

17.6

4

3.84 2.71e05

9.49 0.000677

Beta Poisson

1.72

3

7.81 0.632

BetaPoisson fits better than exponential; cannot reject good fit for betaPoisson.


Optimized parameters for the betaPoisson model, from 10000 bootstrap iterations
Parameter

MLE estimate

Percentiles

0.5% 
2.5% 
5% 
95% 
97.5% 
99.5%

α

9.36E02

1.19E02 
2.03E02 
2.95E02 
1.10E+00 
1.02E+02 
8.41E+02

N_{50}

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
 ↑ ^{1.0} ^{1.1} ^{1.2} Smith, M. A., K. Takeuchi, et al. (2008). "DoseResponse Model for Listeria monocytogenesInduced Stillbirths in Nonhuman Primates." Infection and Immunity 76(2): 726731
 ↑ ^{2.0} ^{2.1} ^{2.2} Williams, D., E. A. Irvin, et al. (2007)."DoseResponse of Listeria monocytogenes after Oral Exposure in Pregnant Guinea Pigs." Journal of Food Protection 70(5): 11221128
Williams D, Castleman J, et al. (2009) Risk of Fetal Mortality After Exposure to Listeria monocytogenes Based on DoseResponse Data from Pregnant Guinea Pigs and Primates. Risk Analysis 29(11): 14951505.