Naegleria fowleri: Dose Response Models

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Naegleria fowleri

Author: Yin Huang


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 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) LD50/ID50
253, 254* [1] mice LEE strain intravenous 7 no of trophozoites death exponential k = 3.42E-07 2.03E+06
253 [2] mice LEE strain intravenous 3 no of trophozoites death exponential k = 4.21E-07 1.64E+06
254 [3] mice LEE strain intravenous 4 no of trophozoites death exponential k = 3.07E-07 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 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

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
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


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
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


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
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



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. 1.0 1.1 COMPLETE REF HERE Cite error: Invalid <ref> tag; name "Adams_et_al._1976_.26_Haggerty_and_John_1978" defined multiple times with different content
  2. 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, 1387-1391.
  3. 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, 73-77.

Adams, A.C., John, D.T. and Bradley, S.G. (1976) Modification of resistance of mice to naegleria fowleri infections. Infection and Immunity 13, 1387-1391.

Haggerty, R.M. and John, D.T. (1978) Innate resistance of mice to experimental infection with naegleria fowleri. Infection and Immunity 20, 73-77.

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, 490-513.