Burkholderia mallei: Dose Response Experiments

General Overview

The bacterium Bukholderia pseudomallei (B. pseudomallei) is a gram negative bacterium and is present in numerous tropical regions such as Central and South America and Southeast Asia causes Melioidosis, typically infects horses, mules and donkeys but can also present a potentially life threatening disease in humans as well. Burkholderia mallei (B. mallei) is a close relative of B. pseudomallei both of which have been categorized as a B level bioterror agent by the CDC. No dose response models are currently available for B. mallei. http://www.cdc.gov/melioidosis/

Liu et al. in 2002 examined infection through intranasal route to mimic infection through inhalation. C57BL/6 mice and BALB/c mice were inoculated intranasally to B. pseudomallei KHW strain and mortality was recorded as response . Miller et al.(1948) explored infection in guinea pigs via intraperitoneal route . Similarly, Brett and Woods(1996) experimented infection in diabetic rats with B. pseuomallei 316c strain .

Recommended Model

Since the data of C57BL/6 mice and diabetic rat could be pooled and intranasal exposure is closer to inhalation which is the likeliest exposure route for humans, the pooled data sets and resulting models is preferred.

ID	Exposure Route	# of Doses	Agent Strain	Dose Units	Host type	Μodel	LD50/ID50	Optimized parameters	Response type	Reference
17	intranasal	5.00	KHW	CFU	BALB/c mice	exponential	6.63E+01	k = 1.04E-02	infection	Liu, B. ., Koo, G. C., Yap, E. H., Chua, K. L., & Y-h, G. . (2002). Model of Differential Susceptibility to Mucosal Burkholderia pseudomallei Infection. Infection and Immunity, 70, 2.
18	intranasal	5.00	KHW	CFU	C57BL/6 mice	exponential	6.92E+03	k = 1.00E-04	infection	Liu, B. ., Koo, G. C., Yap, E. H., Chua, K. L., & Y-h, G. . (2002). Model of Differential Susceptibility to Mucosal Burkholderia pseudomallei Infection. Infection and Immunity, 70, 2.
18,23		10.00	KHW,316c	CFU	C57BL/6 mice and diabetic rat	beta-Poisson	5.43E+03	a = 3.28E-01 N₅₀ = 5.43E+03	death	Brett, P. J., & Woods, D. E. (1996). Structural and immunological characterization of Burkholderia pseudomallei O-polysaccharide-flagellin protein conjugates. Infection and Immunity, 64, 2824–2828.
21	intraperitoneal	6.00	W294	CFU	guinea pig	beta-Poisson	2.55E+02	a = 2.67E-01 N₅₀ = 2.55E+02	death	Miller, W. R., Pannell, L. ., Cravitz, L. ., Tanner, W. A., & Rosebury, T. . (1948). Studies on Certain Biological Characteristics of Malleomyces mallei and Malleomyces pseudomallei. Journal of Bacteriology, 55, 1.
21,23	intraperitoneal	11.00	W294, 316c	CFU	guinea pig and diabetic rat	beta-Poisson	4.77E+02	a = 2.13E-01 N₅₀ = 4.77E+02	death	Miller, W. R., Pannell, L. ., Cravitz, L. ., Tanner, W. A., & Rosebury, T. . (1948). Studies on Certain Biological Characteristics of Malleomyces mallei and Malleomyces pseudomallei. Journal of Bacteriology, 55, 1.
23	intraperitoneal	5.00	316c	CFU	diabetic rat	beta-Poisson	2.27E+03	a = 2.65E-01 N₅₀ = 2.27E+03	death	Brett, P. J., & Woods, D. E. (2000). Pathogenesis of and immunity to melioidosis. Acta Tropica, 74, 2.

Exposure Route:

intranasal

# of Doses:

5.00

Agent Strain:

KHW

Dose Units:

CFU

Host type:

BALB/c mice

Μodel:

exponential

LD50/ID50:

6.63E+01

Optimized parameters: k = 1.04E-02

Response type:

infection

Reference:

Model of Differential Susceptibility to Mucosal Burkholderia pseudomallei Infection

**BALB/c Mice KHW Strain Data**
Dose	Infected	Non-infected	Total
5	0	6	6
15	0	6	6
45	3	1	4
135	4	2	6
405	6	0	6

**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	5.25	-0.000362	4	3.84 1	9.49 0.263
Beta Poisson	5.25	-0.000362	3	3.84 1	7.81 0.154
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

**Optimized parameters 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	1.04E-02	4.94E-03	5.96E-03	6.60E-03	1.92E-02	2.45E-02	2.45E-02
ID50/LD50/ETC*	6.63E+01	2.82E+01	2.82E+01	3.61E+01	1.05E+02	1.16E+02	1.40E+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

Exposure Route:

intranasal

# of Doses:

5.00

Agent Strain:

KHW

Dose Units:

CFU

Host type:

C57BL/6 mice

Μodel:

exponential

LD50/ID50:

6.92E+03

Optimized parameters: k = 1.00E-04

Response type:

infection

Reference:

Model of Differential Susceptibility to Mucosal Burkholderia pseudomallei Infection

**C57BL/6 Mice KHW Strain Data**
Dose	Infected	Non-infected	Total
150	0	6	6
450	1	5	6
1350	1	5	6
4050	3	3	6
12200	3	3	6

**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	3.36	2.17	4	3.84 0.141	9.49 0.499
Beta Poisson	1.19	2.17	3	3.84 0.141	7.81 0.755
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

**Optimized parameters 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	1E-04	2.87E-05	4.15E-05	4.99E-05	1.89E-04	2.13E-04	2.70E-04
ID50/LD50/ETC*	6.92E+03	2.57E+03	3.26E+03	3.68E+03	1.39E+04	1.67E+04	2.41E+04
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

Highest quality

Exposure Route:

# of Doses:

10.00

Agent Strain:

KHW,316c

Dose Units:

CFU

Host type:

C57BL/6 mice and diabetic rat

Μodel:

beta-Poisson

LD50/ID50:

5.43E+03

Optimized parameters: a = 3.28E-01 N₅₀ = 5.43E+03

Response type:

death

Reference:

Structural and immunological characterization of Burkholderia pseudomallei O-polysaccharide-flagellin protein conjugates.

Optimization Output for experiment 18 and 23 pooled (B. pseudomallei)

**Pooled data of C57BL/6 mice and diabetic rat**
Dose	DEATH	NOT DEATH	Total
150	0	6	6
450	1	5	6
1350	1	5	6
3000	6	4	10
4050	3	3	6
12200	3	3	6
3E+04	7	3	10
3E+05	7	3	10
3E+06	10	0	10
3E+07	10	0	10

**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	63.3	56.6	9	3.84 5.42e-14	16.9 3.15e-10
Beta Poisson	6.68	56.6	8	3.84 5.42e-14	15.5 0.571
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	3.28E-01	1.94E-01	2.16E-01	2.31E-01	5.15E-01	5.86E-01	8.32E-01
N₅₀	5.43E+03	1.82E+03	2.37E+03	2.64E+03	1.23E+04	1.39E+04	1.68E+04

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:

intraperitoneal

# of Doses:

6.00

Agent Strain:

W294

Dose Units:

CFU

Host type:

guinea pig

Μodel:

beta-Poisson

LD50/ID50:

2.55E+02

Optimized parameters: a = 2.67E-01 N₅₀ = 2.55E+02

Response type:

death

Reference:

Studies on Certain Biological Characteristics of Malleomyces mallei and Malleomyces pseudomallei

**Guinea Pigs W294 Strain Data**
Dose	Dead	Survived	Total
44	1	4	5
440	3	2	5
4400	4	1	5
44000	5	0	5
440000	5	0	5
4.4E+06	4	1	5

**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	70.3	66.1	5	3.84 4.44e-16	11.1 8.93e-14
Beta Poisson	4.14	66.1	4	3.84 4.44e-16	9.49 0.387
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	2.67E-01	3.36E-02	8.80E-02	1.16E-01	1.05E+01	3.45E+02	3.55E+03
N₅₀	2.55E+02	4.80E-07	2.49E+00	1.48E+01	1.35E+03	1.80E+03	3.22E+03

Exposure Route:

intraperitoneal

# of Doses:

11.00

Agent Strain:

W294, 316c

Dose Units:

CFU

Host type:

guinea pig and diabetic rat

Μodel:

beta-Poisson

LD50/ID50:

4.77E+02

Optimized parameters: a = 2.13E-01 N₅₀ = 4.77E+02

Response type:

death

Reference:

Studies on Certain Biological Characteristics of Malleomyces mallei and Malleomyces pseudomallei

**Pooled data of guinea pig and diabetic rat**
Dose	DEATH	NOT DEATH	Total
44	1	4	5
440	3	2	5
3000	6	4	10
4400	4	1	5
3E+04	7	3	10
44000	5	0	5
3E+05	7	3	10
440000	5	0	5
3E+06	10	0	10
4.4E+06	4	1	5
3E+07	10	0	10

**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	163	152	10	3.84 0	18.3 0
Beta Poisson	10.1	152	9	3.84 0	16.9 0.343
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	2.13E-01	9.14E-02	1.26E-01	1.39E-01	3.38E-01	3.76E-01	5.60E-01
N₅₀	4.77E+02	3.04E+00	1.63E+01	7.19E+01	2.16E+03	2.75E+03	4.44E+03

Exposure Route:

intraperitoneal

# of Doses:

5.00

Agent Strain:

316c

Dose Units:

CFU

Host type:

diabetic rat

Μodel:

beta-Poisson

LD50/ID50:

2.27E+03

Optimized parameters: a = 2.65E-01 N₅₀ = 2.27E+03

Response type:

death

Reference:

Pathogenesis of and immunity to melioidosis

**diabetic rat and 316c strain**
Dose	DEATH	NOT DEATH	Total
3000	6	4	10
3E+04	7	3	10
3E+05	7	3	10
3E+06	10	0	10
3E+07	10	0	10

**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	43.4	39	4	3.84 4.25e-10	9.49 8.61e-09
Beta Poisson	4.39	39	3	3.84 4.25e-10	7.81 0.222
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.

**Optimized parameters for the beta-Poisson model, from 500 bootstrap iterations**
Parameter	MLE estimate	Percentiles
Parameter	MLE estimate	0.5%	2.5%	5%	95%	97.5%	99.5%
α	2.65E-01	7.56E-02	1.30E-01	1.54E-01	4.94E-01	5.69E-01	8.88E-01
N₅₀	2.27E+03	7.58E-02	1.50E+01	5.32E+01	8.62E+03	1.11E+04	1.74E+04

Burkholderia mallei: Dose Response Experiments Dose response experiments

General Overview

Recommended Model

Optimization Output for experiment 18 and 23 pooled (B. pseudomallei)

References