Naegleria fowleri
Author: Yin Huang
General overview
Naegleria is a freeliving amoeboflagellate that has three stages in its life cycle: trophozoite, cyst, and a temporary flagellate stage. Naegleria fowleri, a human pathogen, is thermophilic, tolerating temperatures of 40^{O}C45^{O}C, while another species Naegleria gruberi is nonpathogenic, with an optimal growth temperature of 22^{O}C35^{O}C. Other known nonpathogenic species include Naegleria lovaniensis, Naegleria jadini, and Naegleria australiensis, although Naegleria australiensis italica has been shown to be a highly pathogenic subspecies in experimental animals. Naegleria fowleri is highly pathogenic and death may follow within a few days after the symptom onset (Ma et al. 1990).
Sources for Naegleria have been reported as water, soil, sewage sludge, cooling towers, nasal and throat swabs, hospital hydrothermal pools, and swimming pools. Naegleria fowleri, the most pathogenic species, has been isolated frequently from thermally polluted waters and sewage wastes. Most human infections with Naegleria fowleri have been associated with swimming in warm waters, but also with the sources of tap water and hot baths (Ma et al. 1990).
Summary Data
Adams et al. (1976) challenged three groups of male DUB/ICR mice intravenously with graded doses of Naegleria fowleri LEE strain and the survival was monitored for two weeks.
Haggerty and John (1978) inoculated male DUB/ICR mice with Naegleria fowleri LEE strain via intravenous route and monitored the survival for three weeks.
Experiment serial number 
Reference 
Host type 
Agent strain 
Route 
# of doses 
Dose units 
Response 
Best fit model 
Optimized parameter(s) 
LD_{50}/ID_{50}

253, 254* 
^{[1]} 
mice 
LEE strain 
intravenous 
7 
no of trophozoites 
death 
exponential 
k = 3.42E07 
2.03E+06

253 
^{[2]} 
mice 
LEE strain 
intravenous 
3 
no of trophozoites 
death 
exponential 
k = 4.21E07 
1.64E+06

254 
^{[3]} 
mice 
LEE strain 
intravenous 
4 
no of trophozoites 
death 
exponential 
k = 3.07E07 
2.26E+06

*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 the pooled experiments 253 and 254 should be used as the best doseresponse model. Both strains are common in outbreaks. The pooling narrows the range of the confidence region of the parameter estimates and enhances the statistical precision.
Optimization Output for experiment 253, 254
mice/ Naegleria fowleri LEE strain model data ^{[1]}
Dose 
Dead 
Survived 
Total

1E+06 
4 
16 
20

2.5E+06 
4 
6 
10

2.5E+06 
12 
8 
20

5E+06 
19 
1 
20

5E+06 
14 
6 
20

1E+07 
10 
0 
10

1E+07 
20 
0 
20


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

8.85

0.000501

6

3.84 1

12.6 0.182

Beta Poisson

8.85

5

11.1 0.115

Exponential is preferred to betaPoisson; cannot reject good fit for exponential.


Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter

MLE estimate

Percentiles

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

k 
3.42E07 
2.57E07 
2.75E07 
2.84E07 
4.15E07 
4.34E07 
4.67E07

ID50/LD50/ETC* 
2.03E+06 
1.48E+06 
1.60E+06 
1.67E+06 
2.44E+06 
2.52E+06 
2.70E+06

*Not a parameter of the exponential model; however, it facilitates comparison with other models.


Parameter histogram for exponential model (uncertainty of the parameter) Exponential model plot, with confidence bounds around optimized model
Optimization Output for experiment 253
mice/Naegleria fowleri LEE strain data ^{[2]}
Dose 
Dead 
Survived 
Total

2.5E+06 
4 
6 
10

5E+06 
19 
1 
20

1E+07 
10 
0 
10


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

4.11

9.67

2

3.84 1

5.99 0.128

Beta Poisson

13.8

1

3.84 0.000206

Exponential is preferred to betaPoisson; cannot reject good fit for exponential.


Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter

MLE estimate

Percentiles

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

k 
4.21E07 
2.77E07 
3.04E07 
3.25E07 
5.95E07 
6.79E07 
8.02E07

ID50/LD50/ETC* 
1.64E+06 
8.65E+05 
1.02E+06 
1.16E+06 
2.13E+06 
2.28E+06 
2.50E+06

*Not a parameter of the exponential model; however, it facilitates comparison with other models.


Parameter histogram for exponential model (uncertainty of the parameter) Exponential model plot, with confidence bounds around optimized model
Optimization Output for experiment 254
Mice/Naegleria fowleri LEE strain data ^{[3]}
Dose 
Dead 
Survived 
Total

1E+06 
4 
16 
20

2.5E+06 
12 
8 
20

5E+06 
14 
6 
20

1E+07 
20 
0 
20


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

3.47

0.000862

3

3.84 1

7.81 0.325

Beta Poisson

3.47

2

5.99 0.177

Exponential is preferred to betaPoisson; cannot reject good fit for exponential.


Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter

MLE estimate

Percentiles

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

k 
3.07E07 
2.11E07 
2.31E07 
2.41E07 
3.98E07 
4.21E07 
4.68E07

ID50/LD50/ETC* 
2.26E+06 
1.48E+06 
1.65E+06 
1.74E+06 
2.88E+06 
3.01E+06 
3.28E+06

*Not a parameter of the exponential model; however, it facilitates comparison with other models.


Parameter histogram for exponential model (uncertainty of the parameter) Exponential model plot, with confidence bounds around optimized model
Summary
By increasing the number of data points, the pooling narrows the range of the confidence region of the parameter estimates and enhances the statistical precision.
References
 ↑ ^{1.0} ^{1.1} COMPLETE REF HERE Cite error: Invalid
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 ↑ ^{2.0} ^{2.1} Adams, A.C., John, D.T. and Bradley, S.G. (1976) Modification of resistance of mice to naegleria fowleri infections. Infection and Immunity 13, 13871391.
 ↑ ^{3.0} ^{3.1} Haggerty, R.M. and John, D.T. (1978) Innate resistance of mice to experimental infection with naegleria fowleri. Infection and Immunity 20, 7377.
Adams, A.C., John, D.T. and Bradley, S.G. (1976) Modification of resistance of mice to naegleria fowleri infections. Infection and Immunity 13, 13871391.
Haggerty, R.M. and John, D.T. (1978) Innate resistance of mice to experimental infection with naegleria fowleri. Infection and Immunity 20, 7377.
Ma, P., Visvesvara, G.S., Martinez, A.J., Theodore, F.H., Daggett, P.M. and Sawyer, T.K. (1990) Naegleria and acanthamoeba infections: Review. Reviews of Infectious Diseases 12, 490513.