Giardia duodenalis: Dose Response Models

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Giardia duodenalis

Author: Kyle S. Enger


Overview

Giardia is a flagellated protozoan parasite of vertebrates. It attaches noninvasively to the small intestinal wall and absorbs nutrients (Miliotis & Bier 2003). Cysts are intermittently excreted in the stools of infected people; they are infectious immediately. Giardiasis often presents with diarrhea and flatulence, with foul-smelling foamy stools (Miliotis and Bier 2003). It can often last for 6 to 10 weeks or more without treatment; furthermore, the disease may appear to resolve, only to return later (Miliotis & Bier 2003). Partial immunity appears to develop, and infections are often asymptomatic (Miliotis & Bier 2003). Immunity is incomplete and appears to apply more to symptomatic disease than actual infection (Valentiner-Branth et al. 2003).

The taxonomy of the genus Giardia is somewhat unclear. There have been a variety of species names assigned to pathogenic Giardia in humans, including G. intestinalis, G. enterica, and G. lamblia. The currently accepted name is G. duodenalis (Monis et al. 2009). Although it has been commonly considered a zoonosis, recent evidence indicates that G. duodenalis assemblages A and B (with B sometimes referred to as G. enterica) are more specific to humans (Monis et al. 2009). Dose response relationships vary depending on assemblage and host. It is difficult to distinguish Giardia assemblages morphologically; molecular methods are required (Monis et al. 2009).


Summary of Data

Rendtorff (1954) conducted a series of feeding studies in adult male prisoners. The dose response model that best fits these data is an exponential model with an ID50 of 35 cysts. Essentially the same model fit was obtained by Rose et al. (1991). This model has been found to be consistent with results from an epidemiological study in France of diarrhea and drinking water quality (Zmirou-Navier et al. 2006).

Erlandsen et al. (1969) experimentally infected wild beavers and muskrats with human-derived Giardia cysts. Giardia was much less potent in these experiments (compared to Rendtorff (1954)). This illustrates the necessity of considering assemblage and host when applying a Giardia dose response model.

Another dataset describing Giardia dose response in humans during an outbreak at a ski resort in Colorado has been published (Istre et al. 1984). However, dose is described subjectively as glasses of water consumed, and the concentration of cysts in the water was not measured, so it is not possible to tie the response directly to the numbers of cysts consumed.


Experiment serial number Reference Host type Agent strain Route # of doses Dose units Response Best fit model Optimized parameter(s) LD50/ID50
46* [1] human From an infected human oral 8 Cysts infection exponential k = 1.99E-02 3.48E+01
48 [2] muskrat From infected humans stomach tube 5 Cysts infection exponential k = 3.68E-06 1.89E+05
47 [3] beaver From infected humans oral 4 Cysts infection beta-Poisson α = 1.37E-01 , N50 = 1.46E+04 1.46E+04
*This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.

Recommendations

For most risk applications in humans, the model fit to experiment 46 is preferable. However, the other models may be useful for describing zoonotic Giardia infection.


Exponential and betapoisson model.jpg

Optimization Output for experiment 46

Dose response data [1]
Dose Infected Non-infected Total
1 0 5 5
10 2 0 2
25 6 14 20
100 2 0 2
1E+04 3 0 3
1E+05 3 0 3
3E+05 3 0 3
1E+06 2 0 2


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 8.37 -0.000469 7 3.84
1
14.1
0.301
Beta Poisson 8.37 6 12.6
0.212
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 1.99E-02 8.50E-03 1.05E-02 1.26E-02 2.92E-02 3.29E-02 3.71E-02
ID50/LD50/ETC* 3.48E+01 1.87E+01 2.11E+01 2.38E+01 5.49E+01 6.60E+01 8.15E+01
*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 48

Dose response data [2]
Dose Infected Non-infected Total
30 0 8 8
300 0 7 7
3E+04 0 6 6
125000 2 1 3
5E+05 4 1 5


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 2.49 0.0417 4 3.84
0.838
9.49
0.646
Beta Poisson 2.45 3 7.81
0.484
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 3.68E-06 1.13E-06 1.35E-06 1.88E-06 9.60E-06 9.60E-06 9.60E-06
ID50/LD50/ETC* 1.89E+05 7.22E+04 7.22E+04 7.22E+04 3.68E+05 5.14E+05 6.14E+05
*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 47

Dose response data [3]
Dose Infected Non-infected Total
48 0 6 6
454 2 4 6
4460 1 2 3
550000 2 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 22.5 21.3 3 3.84
3.97e-06
7.81
5.14e-05
Beta Poisson 1.22 2 5.99
0.544
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.


Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.37E-01 1.34E-02 2.24E-02 4.22E-02 3.39E+00 2.21E+02 2.14E+03
N50 1.46E+04 5.09E+02 8.20E+02 1.06E+03 1.71E+08 8.25E+11 1.62E+18


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. 1.0 1.1 Rendtorff, R.C., 1954. The experimental transmission of human intestinal protozoan parasites. II. Giardia lamblia cysts given in capsules. American Journal of Epidemiology, 59(2), pp.209-220.
  2. 2.0 2.1 Erlandsen, S.L. et al., 1988. Cross-species transmission of Giardia spp.: inoculation of beavers and muskrats with cysts of human, beaver, mouse, and muskrat origin. Appl. Environ. Microbiol., 54(11), pp.2777-2785.
  3. 3.0 3.1 Erlandsen, S.L. et al., 1988. Cross-species transmission of Giardia spp.: inoculation of beavers and muskrats with cysts of human, beaver, mouse, and muskrat origin. Appl. Environ. Microbiol., 54(11), pp.2777-2785.

Erlandsen, S.L. et al., 1988. Cross-species transmission of Giardia spp.: inoculation of beavers and muskrats with cysts of human, beaver, mouse, and muskrat origin. Appl. Environ. Microbiol., 54(11), pp.2777-2785.  

Istre, G.R. et al., 1984. Waterborne giardiasis at a mountain resort: evidence for acquired immunity. American Journal of Public Health, 74(6), pp.602-604.  

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

Monis, P.T., Caccio, S.M. & Thompson, R.C.A., 2009. Variation in Giardia: towards a taxonomic revision of the genus. Trends in Parasitology, 25(2), pp.93-100.  

Rendtorff, R.C., 1954. The experimental transmission of human intestinal protozoan parasites. II. Giardia lamblia cysts given in capsules. American Journal of Epidemiology, 59(2), pp.209-220.  

Rose, J.B., Haas, C.N. & Regli, S., 1991. Risk assessment and control of waterborne giardiasis. American Journal of Public Health, 81(6), pp.709-713.  

Valentiner-Branth, P. et al., 2003. Cohort study of Guinean children: incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life. Journal of Clinical Microbiology, 41(9), pp.4238-4245.  

Zmirou-Navier D, Gofti-Laroche L and Hartemann P (2006) Waterborne microbial risk assessment: a population-based dose-response function for Giardia spp.(E.MI.R.A study). BMC Public Health. 6 (1), 122.