Mycobacterium avium: Dose Response Experiments

General Overview

Mycobacterium avium subsp. paratuberculosis (MAP) is an obligate pathogenic bacterium of the genus Mycobacterium which causes chronic inflammation of the intestine in domestic and wild ruminants as well as other animals, including primates. M. avium subsp.paratuberculosis can live in animals for years without necessarily causing clinical disease. Infection is widespread in domestic livestock in Europe and North America but can occur elsewhere.

Summary Data

O’Brien et al.(1976) exposed three groups of newly weaned 4-month-old red deer orally with M. avium subsp. paratuberculosis Bovine strain and necropsy was conducted 44 weeks post inoculation to determine the infection rate.

Brotherston et al. (1976) inoculated South Country Cheviots at the age of three weeks orally with M. avium subsp. paratuberculosis IOI strain which was originally recovered from a clinical case of the disease in a sheep and VB/4 strain from an affected cow. The necropsy was done 1-9 months post inoculation.

Recommended Model

Experiment number 262 model is the recommended model. The ID50 of the model has lower value than the other model.

Exponential and betapoisson model.jpg

ID	Exposure Route	# of Doses	Agent Strain	Dose Units	Host type	Μodel	LD50/ID50	Optimized parameters	Response type	Reference
262	oral	3.00	sub sp. Paratuberculosis Bovine	CFU	deer	exponential	1000	k = 6.93E-04	infection	Nisbet, D. I., Gilmour, N. J., & Brotherston, J. G. (1962). Quantitative studies of Mycobacterium johnei in tissues of sheep. III. Intestinal histopathology. Journal of Comparative Pathology, 72, 80.
263	oral	3.00	sub sp. Paratuberculosis IOI strain	CFU	cheviots	beta-Poisson	4.8E+02	a = 5.79E-02 N₅₀ = 4.8E+02	infection	Badenoch, P. R., Johnson, A. M., Christy, P. E., & Coster, D. J. (1990). Pathogenicity of Acanthamoeba and Corynebacterium in the Rat Cornea. Archives of Ophthalmology, 108, 1. Retrieved from https://jamanetwork.com/journals/jamaophthalmology/article-abstract/638228
myco_intratracheal	Intratracheal inoculation	3.00	MAC serotype 8 (Human-derived, AIDS Patient)	CFU	hamsters	beta-Poisson	1.42E+8	a = 0.201 k = 4.87E-9 N₅₀ = 1.42E+8	Disseminated infection
myco_intratracheal_2	Intratracheal inoculation	3.00	MAC serotype 8 (Human-derived, AIDS Patient)	CFU	hamsters	beta-Poisson	7.93E+8	a = 0.048 N₅₀ = 7.93E+8	Liver infection
myco_intravenous	intravenous	5.00	M. avium serovar 1, human non- AIDS isolates: pooled strains N-289, N-356, N-357, N-364, N-445, N458, N-461; Serovar 9 strains N-254, N-302	CFU	mice	exponential	6.30E+5	k = 1.10E-6	Lung lesions
myco_intravenous_2	intravenous	5.00	MAC 101 (human-derived)	CFU	mice	exponential	2.22E+8	k = 3.12E-9	death
myco_intravenous_3	intravenous	15.00	M. avium serotype II strain SSC 1323 (porcine-derived	CFU	pig	exponential	7.49E+7	k = 9.26E-9	Lesions or culture in lymph nodes
myco_intravenous_3	intravenous	15.00	M. avium serotype II strain SSC 1323 (porcine-derived)	CFU	pig	exponential	8.79E+6	k = 7.88E-8	Lesions or culture in lymph nodes
myco_intravenous_4	intravenous	15.00		CFU	pig	exponential	4.19E+7	k = 1.65E-8	Lesions or culture in lymph nodes

Highest quality

Exposure Route:

oral

# of Doses:

3.00

Agent Strain:

sub sp. Paratuberculosis Bovine

Dose Units:

CFU

Host type:

deer

Μodel:

exponential

LD50/ID50:

1000

Optimized parameters: k = 6.93E-04

Response type:

infection

Reference:

Quantitative studies of Mycobacterium johnei in tissues of sheep. III. Intestinal histopathology

**Dose response data**
Dose	Infected	Non-infected	Total
1000	8	8	16
1E+07	16	0	16
1E+09	16	0	16

**Goodness of fit and model selection**
Model	Deviance	Δ	Degrees of freedom	χ²_0.95,1 p-value	χ²_0.95,m-k p-value
Exponential	3.07e-05	7.15e-06	2	3.84 0.998	5.99 1
Beta Poisson	2.36e-05	7.15e-06	1	3.84 0.998	3.84 0.996
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
Parameter	MLE estimate	0.5%	2.5%	5%	95%	97.5%	99.5%
k	6.93E-04	2.08E-04	2.88E-04	3.75E-04	1.16E-03	1.39E-03	1.67E-03
ID50/LD50/ETC*	1E+03	4.14E+02	5.00E+02	5.96E+02	1.85E+03	2.41E+03	3.34E+03
*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

Exposure Route:

oral

# of Doses:

3.00

Agent Strain:

sub sp. Paratuberculosis IOI strain

Dose Units:

CFU

Host type:

cheviots

Μodel:

beta-Poisson

LD50/ID50:

4.8E+02

Optimized parameters: a = 5.79E-02 N₅₀ = 4.8E+02

Response type:

infection

Reference:

Pathogenicity of Acanthamoeba and Corynebacterium in the Rat Cornea

**Dose response data**
Dose	Infected	Non-infected	Total
100	6	6	12
1E+05	6	6	12
1E+08	10	2	12

**Goodness of fit and model selection**
Model	Deviance	Δ	Degrees of freedom	χ²_0.95,1 p-value	χ²_0.95,m-k p-value
Exponential	193	192	2	3.84 0	5.99 0
Beta Poisson	1.43	192	1	3.84 0	3.84 0.231
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
Parameter	MLE estimate	0.5%	2.5%	5%	95%	97.5%	99.5%
α	5.79E-02	9.94E-04	9.78E-03	1.25E-02	1.27E-01	1.42E-01	1.87E-01
N₅₀	4.8E+02	3.44E-13	5.25E-08	1.89E-05	5.61E+04	1.50E+05	4.41E+06

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

Exposure Route:

Intratracheal inoculation

# of Doses:

3.00

Agent Strain:

MAC serotype 8 (Human-derived, AIDS Patient)

Dose Units:

CFU

Host type:

hamsters

Μodel:

beta-Poisson

LD50/ID50:

1.42E+8

Optimized parameters: a = 0.201 k = 4.87E-9 N₅₀ = 1.42E+8

Response type:

Disseminated infection

Reference:

Exposure Route:

Intratracheal inoculation

# of Doses:

3.00

Agent Strain:

MAC serotype 8 (Human-derived, AIDS Patient)

Dose Units:

CFU

Host type:

hamsters

Μodel:

beta-Poisson

LD50/ID50:

7.93E+8

Optimized parameters: a = 0.048 N₅₀ = 7.93E+8

Response type:

Liver infection

Reference:

Exposure Route:

intravenous

# of Doses:

5.00

Agent Strain:

M. avium serovar 1, human non- AIDS isolates: pooled strains N-289, N-356, N-357, N-364, N-445, N458, N-461; Serovar 9 strains N-254, N-302

Dose Units:

CFU

Host type:

mice

Μodel:

exponential

LD50/ID50:

6.30E+5

Optimized parameters: k = 1.10E-6

Response type:

Lung lesions

Reference:

Exposure Route:

intravenous

# of Doses:

5.00

Agent Strain:

MAC 101 (human-derived)

Dose Units:

CFU

Host type:

mice

Μodel:

exponential

LD50/ID50:

2.22E+8

Optimized parameters: k = 3.12E-9

Response type:

death

Reference:

Exposure Route:

intravenous

# of Doses:

15.00

Agent Strain:

M. avium serotype II strain SSC 1323 (porcine-derived

Dose Units:

CFU

Host type:

pig

Μodel:

exponential

LD50/ID50:

7.49E+7

Optimized parameters: k = 9.26E-9

Response type:

Lesions or culture in lymph nodes

Reference:

Exposure Route:

intravenous

# of Doses:

15.00

Agent Strain:

M. avium serotype II strain SSC 1323 (porcine-derived)

Dose Units:

CFU

Host type:

pig

Μodel:

exponential

LD50/ID50:

8.79E+6

Optimized parameters: k = 7.88E-8

Response type:

Lesions or culture in lymph nodes

Reference:

Exposure Route:

intravenous

# of Doses:

15.00

Agent Strain:

Dose Units:

CFU

Host type:

pig

Μodel:

exponential

LD50/ID50:

4.19E+7

Optimized parameters: k = 1.65E-8

Response type:

Lesions or culture in lymph nodes

Reference:

Mycobacterium avium: Dose Response Experiments Dose response experiments

General Overview

Summary Data

Recommended Model

References