Adenovirus: Dose Response Models

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Adenovirus

Author: Sushil Tamrakar


Overview of Adenovirus

Adenoviruses are medium-sized (90-100 nm), nonenveloped (naked) icosohedral viruses containing double-stranded DNA. There are more than 52 immunologically distinct types that can cause infections in humans and animals. Adenoviruses are unusually stable to chemical and physical agents and to adverse pH conditions, thus allowing for prolonged survival outside of the body(CDC 2010).

Adenoviruses most commonly cause respiratory illness the most commoncause of acute infectious disease in U.S. adults (Gray, Callahan et al. 1999) however, depending on the infecting serotype, they also cause various other illnesses, such as gastroenteritis, conjunctivitis, cystitis (bladder infection), and rash illness. Symptoms of respiratory illness caused by adenovirus infection range from the common cold syndrome to pneumonia, croup, and bronchitis (CDC 2010).

Acute respiratory disease (ARD), which was first recognized among military recruits during World War II, caused by adenovirus infections (Gray, Callahan et al. 1999; CDC 2010). Although epidemiologic characteristics of the adenoviruses vary by type, all are transmitted by direct contact, fecal-oral transmission, and waterborne transmission.

ARD is most often associated with adenovirus types 4 and 7, and more recently adenovirus 14, in the United States. Enteric adenoviruses 40 and 41 cause gastroenteritis, usually in children. For some adenovirus serotypes, the clinical spectrum of disease associated with infection varies depending on the site of infection; for example, infection with adenovirus 7 acquired by inhalation is associated with severe lower respiratory tract disease, whereas oral transmission of the virus typically causes no or mild disease(CDC 2010).



Summary of data

Couch, R. B., T. R. Cate, et al. (1966). "Effect of route of inoculation on experimental respiratory viral disease in volunteers and evidence for airborne transmission." Microbiol. Mol. Biol. Rev. 30(3): 517-529.- In this study, several healthy adult male volunteers were exposed to aerosols containing adenovirus type 4 (Couch, Cate et al. 1966).

Couch, R. B., V. Knight, et al. (1969). "The minimal infectious dose of adenovirus type 4; the case for natural transmission by viral aerosol.." Trans Am Clin Climatol Assoc. 80: 205-211.- In this study, human volunteers were inoculated intaranasally with adenovirus type 4 (Couch, Knight et al. 1969).


Experiment serial number Reference Host type Agent strain Route # of doses Dose units Response Best fit model Optimized parameter(s) LD50/ID50
31* [1] human type 4 inhalation 4 TCID50 infection exponential k = 6.07E-01 1.14E+00
255 [2] human type 4 intranasal 5 TCID50 infection exponential k = 1.51E-02 4.59E+01
*This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.


Exponential and betapoisson model.jpg

Optimization Output for experiment 31

Humans/ type 4 Strain model data [1]
Dose Infected Non-infected Total
1 1 2 3
5 3 0 3
11 3 0 3
1000 6 0 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 0.487 -0.000723 3 3.84
1
7.81
0.922
Beta Poisson 0.488 2 5.99
0.784
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 6.07E-01 3.87E-01 3.87E-01 3.87E-01 1.13E+00 1.13E+00 1.13E+00
ID50/LD50/ETC* 1.14E+00 6.11E-01 6.11E-01 6.11E-01 1.79E+00 1.79E+00 1.79E+00
*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 255

Humans/ type 4 Strain model data [2]
Dose Infected Non-infected Total
3 0 6 6
10 0 2 2
14 1 1 2
79 2 1 3
400 3 0 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 2.14 -0.00118 4 3.84
1
9.49
0.71
Beta Poisson 2.14 3 7.81
0.544
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 1.51E-02 4.00E-03 5.88E-03 6.35E-03 4.56E-02 4.56E-02 4.56E-02
ID50/LD50/ETC* 4.59E+01 1.52E+01 1.52E+01 1.52E+01 1.09E+02 1.18E+02 1.73E+02
*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



References

  1. 1.0 1.1 Couch, R. B., T. R. Cate, et al. (1966). "Effect of route of inoculation on experimental respiratory viral disease in volunteers and evidence for airborne transmission." Microbiol. Mol. Biol. Rev. 30(3): 517-529.
  2. 2.0 2.1 Couch, R. B., V. Knight, et al. (1969). "The minimal infectious dose of adenovirus type 4; the case for natural transmission by viral aerosol." Trans Am Clin Climatol Assoc. 80: 205-211.

CDC (2010). Adenoviruses, CDC, Division of Viral Diseases.

Couch, R. B., T. R. Cate, et al. (1966). "Effect of route of inoculation on experimental respiratory viral disease in volunteers and evidence for airborne transmission." Microbiol. Mol. Biol. Rev. 30(3): 517-529.

Couch, R. B., V. Knight, et al. (1969). "The minimal infectious dose of adenovirus type 4; the case for natural transmission by viral aerosol." Trans Am Clin Climatol Assoc. 80: 205-211.

Gray, G. C., J. D. Callahan, et al. (1999). "Respiratory diseases among U.S. military personnel: countering emerging threats." Emerging Infectious Diseases 5(3): 379-385.