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General overview

Naegleria is a free-living 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 40OC-45OC, while another species Naegleria gruberi is nonpathogenic, with an optimal growth temperature of 22OC-35OC. Other known nonpathogenic species include Naegleria lovaniensisNaegleria 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.

Recommended Model

It is recommended that the pooled experiments 253 and 254 should be used as the best dose-response 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.

Exponential and betapoisson model.jpg

 

ID # of Doses Agent Strain Dose Units Host type Μodel Optimized parameters Response type Reference
253 3 LEE strain no of trophozoites mice exponential
k = 4.21E-07
LD50/ID50 = 1.64E+06

death Susceptibility of Wild Mammals to Infection with Naegleria fowleri
253, 254 7 LEE strain no of trophozoites mice exponential
k = 3.42E-07
LD50/ID50 = 2.03E+06

death
254 4 LEE strain no of trophozoites mice exponential
k = 3.07E-07
LD50/ID50 = 2.26E+06

death Effect of route of inoculation on experimental respiratory viral disease in volunteers and evidence for airborne transmission
Experiment ID:
253
# of Doses:
3
Agent Strain:
LEE strain
Dose Units:
no of trophozoites
Host type:
mice
Μodel:
exponential
Optimized parameters:
k = 4.21E-07
LD50/ID50 = 1.64E+06

Reference:
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
χ20.95,1 
p-value
χ20.95,m-k 
p-value
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 beta-Poisson; 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 4.21E-07 2.77E-07 3.04E-07 3.25E-07 5.95E-07 6.79E-07 8.02E-07
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

Best Fit
Experiment ID:
253, 254
# of Doses:
7
Agent Strain:
LEE strain
Dose Units:
no of trophozoites
Host type:
mice
Μodel:
exponential
Optimized parameters:
k = 3.42E-07
LD50/ID50 = 2.03E+06

Reference:
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
χ20.95,1 
p-value
χ20.95,m-k 
p-value
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 beta-Poisson; 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 3.42E-07 2.57E-07 2.75E-07 2.84E-07 4.15E-07 4.34E-07 4.67E-07
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

Experiment ID:
254
# of Doses:
4
Agent Strain:
LEE strain
Dose Units:
no of trophozoites
Host type:
mice
Μodel:
exponential
Optimized parameters:
k = 3.07E-07
LD50/ID50 = 2.26E+06

Reference:
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
χ20.95,1 
p-value
χ20.95,m-k 
p-value
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 beta-Poisson; 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 3.07E-07 2.11E-07 2.31E-07 2.41E-07 3.98E-07 4.21E-07 4.68E-07
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