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Teunis, P.F., Nagelkerke, N.J. & Haas, C.N., 1999. [http://www.springerlink.com/index/J5565463825R3R06.pdf Dose response models for infectious gastroenteritis.] ''Risk Analysis: An Official Publication of the Society for Risk Analysis'', 19(6), pp.1251-1260.  
 
Teunis, P.F., Nagelkerke, N.J. & Haas, C.N., 1999. [http://www.springerlink.com/index/J5565463825R3R06.pdf Dose response models for infectious gastroenteritis.] ''Risk Analysis: An Official Publication of the Society for Risk Analysis'', 19(6), pp.1251-1260.  
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[[Category:Dose Response Model]]

Revision as of 21:45, 11 November 2011

Cryptosporidium parvum and Cryptosporidium hominis

Author: Kyle S. Enger
If you want to download this chapter in pdf format, please click here
If you want to download the excel spreadsheet of tables, please click the captions of tables. If you want to download a specific figure, just click on the figure


Overview

Various species of Cryptosporidium infect most vertebrates. C. parvum infects cattle but can also infect humans; C. hominis appears to be restricted to humans, and began to be recognized in the early 2000s (Hunter 2005). The oocysts are the infective stage and are about 5 microns in size; they are excreted in feces and are transmitted to new hosts by the fecal-oral route. They are highly resistant to chlorine, and can survive for months in cold lakes/streams, as well as freezing at -15C for 8-24h (AWWA 1999). They can be inactivated by heat >64.2C for 2+ minutes, or drying at 18-28C for >4h, and they are also vulnerable to ultraviolet light (AWWA 1999). The durability and infectiousness of the oocysts, as well as their documented ability to cause large outbreaks (Mac Kenzie et al., 1994), means that control of Cryptosporidium is very important for drinking water treatment. Water treatment utilities should consider all surface water to be contaminated with oocysts (AWWA 1999). Effective control of Cryptosporidium is generally achieved in drinking water treatment through filtration yielding nonturbid water (<= 0.1 nephelometric turbidity unit) (AWWA 1999).

Cryptosporidiosis is generally a short, self-limited watery diarrhea with an incubation period of 3 to 7 days (Miliotis & Bier 2003). Asymptomatic infections are also common in apparently healthy children and adults (Blaser 2002). However, the disease is particularly dangerous to people with AIDS because there is no effective treatment (Miliotis & Bier 2003). This can lead to lethal infections, or chronic disease lasting months or years that severely damages the gut.




Summary of Data

Cryptosporidium hominis

Chappell et al. (2006) describe a feeding study of C. hominis in adult humans. Although infection and diarrhea were both measured, only diarrhea approximated an increasing response with dose. This is in contrast to the subsequent model fits for C. parvum, all of which use infection as the response.

Cryptosporidium parvum

An experiment (DuPont et al., 1995) from feeding an isolate from a calf (Iowa isolate) to human volunteers yields an exponential model with an ID50 of 165 oocysts (Teunis 1999), which is essentially the same as the model presented here.

Messner et al. (2001) describe dose response model fits using data from other studies that did not themselves publish the experimental datasets:

  • Reanalysis of stool samples from the above experiment (DuPont et al., 1995) using flow cytometry revealed that 2 individuals thought to be uninfected were actually infected (Messner 2001).
  • Two other feeding studies (Okhuysen et al., 1999) in human volunteers using different isolates yielded models with ID50s of 179 oocysts (UCP isolate, also from a calf) and 9 oocysts (TAMU isolate, from an infected veterinary student).

Messner et al. (2001) fit the exponential model to these three datasets. This is appropriate for the Iowa and TAMU isolates, but the beta-Poisson model fits better than the exponential model for the UCP isolate. The UCP and TAMU datasets are smaller than the Iowa datasets.

Okhuysen et al. (2002) also conducted a feeding study in adult humans using C. parvum originating from red deer (Moredun isolate).

Chappell et al. (1999) also conducted a feeding study in humans using the Iowa isolate of C. parvum. Although the data were not published, they estimated an ID50 of 83 oocysts for volunteers lacking anti-C. parvum IgG, and an ID50 of 1,880 oocysts for volunteers who had anti-C. parvum IgG.

Table 1.1. Summary of data.
Experiment number Reference Host type/Pathogen strain Route Dose units Response Best Fit Model Optimized parameters ID50
Cryptosporidium hominis
1 Chappell et al. 2006 Adult humans/TU502 isolate Oral Oocysts Diarrhea Beta-Poisson α = 0.27
N50 = 16.82
16.82
Cryptosporidium parvum
2 DuPont et al., 1995 Adult humans/Iowa isolate Oral Oocysts Infection Exponential k = 4.19E-03 165.39
3 Messner et al., 2001 Adult humans/Iowa isolate Oral Oocysts Infection Exponential k = 5.26E-03 131.80
4 Adult humans/TAMU isolate Oral Oocysts Infection Exponential k = 0.057 12.11
5 Okhuysen et al., 2002 Adult humans/Moredun isolate Oral Oocysts Infection Beta-Poisson α = 0.044
N50 = 16.65
16.65



Optimized Models and Fitting Analyses

Optimization Output for experiment 1

Table 1.2. TU502 data
Dose Infected Non-infected Total
10 2 3 5
30 3 2 5
100 5 2 7
500 3 1 4
Chappell CL et al. 2006.


Table 1.3. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 11.59 11.47 3 3.84
7.00E-04
7.81
0.0089
Beta Poisson 0.12 2 5.99
0.942
Beta Poisson is best fitting model
Table 1.4: Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 0.27 -- -- -- -- -- --
N50 16.82 -- -- -- -- -- --
LD50(spores) 16.82 6.34E-11 2.86E-07 5.87E-06 94.16 169.07 3377.70


Figure 1.1 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
Figure 1.2 beta Poisson model plot, with confidence bounds around optimized model



Optimized Models and Fitting Analyses

Optimization Output for experiment 2

Table 1.5 Iowa strain data
Dose Infected Non-infected Total
3.00E+01 1 4 5
1.00E+02 3 5 8
3.00E+02 2 1 3
5.00E+02 5 1 6
1.00E+03 2 0 2
1.00E+04 3 0 3
1.00E+05 1 0 1
1.00E+06 1 0 1
DuPont et al. 1995.


Table 1.6. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 0.50 0.13 7 3.84
0.717
14.07
0.999
Beta Poisson 0.37 6 12.59
0.999
Exponential is best fitting model
Table 1.7: Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations
Parameter or value MLE estimate Percentiles
0.50% 2.5% 5% 95% 97.5% 99.5%
k 4.19E-03 0.0018 0.0022 0.0025 0.0075 0.0087 0.012
LD50 (spores) 165.39 58.04 79.64 92.20 280.03 312.37 384.43


Figure 1.3 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 1.4 Exponential model plot, with confidence bounds around optimized model



Optimized Models and Fitting Analyses

Optimization Output for experiment 3

Table 1.8 Iowa isolate data
Dose Infected Non-infected Total
3.00E+01 2 3 5
1.00E+02 4 4 8
3.00E+02 2 1 3
5.00E+02 5 1 6
1.00E+03 2 0 2
1.00E+04 3 0 3
1.00E+05 1 0 1
1.00E+06 1 0 1
Messner et al. 2001


Table 1.9. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 3.07 2.00 7 3.84
0.157
14.07
0.879
Beta Poisson 1.07 6 12.59
0.983
Exponential is best fitting model
Table 1.10: Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations
Parameter or value MLE estimate Percentiles
0.50% 2.5% 5% 95% 97.5% 99.5%
k 5.26E-03 0.0022 0.0027 0.0030 0.011 0.012 0.018
LD50 (spores) 131.80 39.46 55.79 65.20 231.22 255.55 313.98


Figure 1.5 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 1.6 Exponential model plot, with confidence bounds around optimized model



Optimized Models and Fitting Analyses

Optimization Output for experiment 4

Table 1.11. TAMU data
Dose Dead Survived Total
10 2 1 3
30 2 1 3
100 3 0 3
500 5 0 5
Messner et al. 2001.


Table 1.12. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 1.07 0.21 3 3.84
0.647
7.81
0.783
Beta Poisson 0.86 2 5.99
0.649
Exponential is best fitting model
Table 1.13: Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations
Parameter or value MLE estimate Percentiles
0.50% 2.5% 5% 95% 97.5% 99.5%
k 0.057 0.018 0.025 0.027 2.32 2.32 2.32
LD50 (spores) 12.11 0.30 0.30 0.30 26.07 28.22 38.42


Figure 1.7 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 1.8 Exponential model plot, with confidence bounds around optimized model



Optimized Models and Fitting Analyses

Optimization Output for experiment 5

Table 1.14. Moredunn isolate data
Dose Dead Survived Total
3.00E+03 3 1 4
1.00E+02 2 2 4
3.00E+02 2 3 5
1.00E+03 1 2 3
3.00E+03 3 1 4
Okhuysen et al. 2002.


Table 1.15. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 8.02 5.95 4 3.84
0.0147
9.49
0.091
Beta Poisson 2.07 3 7.81
0.558
Beta Poisson is best fitting model
Table 1.16: Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 0.044 -- -- -- -- -- --
N50 16.65 -- -- -- -- -- --
LD50(spores) 16.65 4.45E-10 8.21E-06 5.97E-04 947.28 1128.36 1446.97


Figure 1.9 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
Figure 1.10 beta Poisson model plot, with confidence bounds around optimized model



References

Blaser, M.J. et al., eds. 2002. Infections of the Gastrointestinal Tract 2nd ed., Philadelphia: Lippincott Williams & Wilkins.  

Chappell, C.L. et al., 1999. Infectivity of Cryptosporidium parvum in healthy adults with pre-existing anti-C. parvum serum immunoglobulin G. The American Journal of Tropical Medicine and Hygiene, 60(1), pp.157-164.  

Chappell, C.L. et al., 2006. Cryptosporidium hominis: experimental challenge of healthy adults. The American Journal of Tropical Medicine and Hygiene, 75(5), pp.851-857.

DuPont, H.L. et al., 1995. The infectivity of Cryptosporidium parvum in healthy volunteers. The New England Journal of Medicine, 332(13), pp.855-859.  

Hunter, P.R. & Thompson, R.C.A., 2005. The zoonotic transmission of Giardia and Cryptosporidium. International Journal for Parasitology, 35(11-12), pp.1181-1190.  

Mac Kenzie, W.R. et al., 1994. A massive outbreak in Milwaukee of cryptosporidium infection transmitted through the public water supply. The New England Journal of Medicine, 331(3), pp.161-167.  

Messner, M.J., Chappell, C.L. & Okhuysen, P.C., 2001. Risk assessment for Cryptosporidium: a hierarchical Bayesian analysis of human dose response data. Water Research, 35(16), pp.3934-3940.  

Miliotis, M., & Bier, J., eds. 2003. International Handbook of Foodborne Pathogens, New York: M. Dekker.  

Okhuysen, P.C. et al., 1999. Virulence of three distinct Cryptosporidium parvum isolates for healthy adults. The Journal of Infectious Diseases, 180(4), pp.1275-1281.

Okhuysen, P.C. et al., 2002. Infectivity of a Cryptosporidium parvum isolate of cervine origin for healthy adults and interferon-gamma knockout mice. The Journal of Infectious Diseases, 185(9), pp.1320-1325.

Teunis, P.F., Nagelkerke, N.J. & Haas, C.N., 1999. Dose response models for infectious gastroenteritis. Risk Analysis: An Official Publication of the Society for Risk Analysis, 19(6), pp.1251-1260.