View source for Coxiella burnetii: Dose Response Models

==<center>'''Coxiella burnetii'''''</center>==
<center><big>'''Yin Huang'''</big></center>

==='''General overview of ''Coxiella burnetii'' and Q fever'''===

''Coxiella burnetii'' (''C. burnetii''), an obligate intracellular gram-negative bacterium, is the causative agent of Q fever. ''C. burnetii'' multiplies only within the phagolysosomal vacuoles, particularly the macrophages of the host. During natural infections, the organism grows to high numbers in placental tissues of animals such as goats, sheep, and cows. The U.S. Centers for Disease Control and Prevention (CDC) has classified ''C. burnetii'' as a category B biological terrorist agent because it consistently causes disability, can be manufactured on a large scale, remains stable under production, storage, and transportation conditions, can be efficiently disseminated and remains viable for years after dissemination.

Q fever, a zoonotic disease found worldwide, may manifest as acute or chronic disease. The acute form is generally not fatal and manifests as self-controlled febrile illness. Chronic Q fever is usually characterized by endocarditis. Many mamalian models, including humans, have been studied for Q fever infection through various exposure routes.

Humans are infected primarily through inhalation of aerosolized ''C. burnetii''. Aerosols, or airborne particles, easily cause infection even without contact with infected animals, whereas person-to-person infection is rare. Ingestion of contaminated dairy products or bites from infected ticks may also lead to infection but these modes of transmission are very rare. However, there have been some recorded cases of human Q fever caused by the consumption of unpasteurized goat's milk products <ref>Tamrakar SB, Haluska A, Haas CN and  Bartrand BA (2011) Dose-Response Model of Coxiella burnetii (Q Fever). Risk Analysis. 31(1), 120-128.</ref>

http://www.cdc.gov/qfever/

Williams and Cantrell (1982)<ref name="Williams et al, 1982">Williams JC and Cantrell JL (1982) Biological and immunological properties of Coxiella burnetii vaccines in C57BL/1OScN endotoxin-nonresponder mice. Infection and Immunity 35(3), 1091–1102.</ref> intraperitoneally inoculated groups of C57BL/10ScN male mice by ''C. burnetii'' phase I Ohio strain to develop a vaccine against Q fever.

Scott and Williams (1987) <ref name="Scott et al, 1987">Scott G, Williams JC, Stephenson EH (1987) Animal models in Q fever: pathological responses of inbred mice to phase I Coxiella Burnetii. Journal of General Microbiology. 133(3), 691–700.</ref>examined the susceptibility of inbred mice to infection by ''C. burnetii ''Nine mile phase I strain. As many as 47 strains of inbred mice were evaluated. Groups of resistant C57BL/6J mice were inoculated with mean doses ranging from 10<sup>−1.3</sup> to 10<sup>7</sup> organisms. The mortalities at various doses were recorded.

The apparent difference of LD<sub>50</sub> between the experiment 28 (4.93x10<sup>8</sup>) and experiment 26 (1.22 x10<sup>10</sup>) routes while are similar may be associated with differences in susceptible hosts and pathogen strains.


{{DRSummaryTableStart|agent=''Coxiella burnetii''}}
{{DRSummaryTablePreferredModel|expID= 28|refer=Williams et al, 1982|reference=Williams JC and Cantrell JL (1982) Biological and immunological properties of Coxiella burnetii vaccines in C57BL/1OScN endotoxin-nonresponder mice. Infection and Immunity 35(3), 1091–1102.|host= C57BL/1OScN mice |agentStrain= phase I Ohio |route= intraperitoneal |nDoses= 10 |doseUnits= PFU |response= death |bestFitModel=beta-Poisson|parameters=&alpha;=  3.57E-01 , N<sub>50</sub> =  4.93E+08 |N50= 4.93E+08 }}
{{DRSummaryNonpreferredModel|expID= 26 |refer =Scott et al, 1987|reference=Scott G, Williams JC, Stephenson EH (1987) Animal models in Q fever: pathological responses of inbred mice to phase I Coxiella Burnetii. Journal of General Microbiology. 133(3), 691–700.|host= C57BL/6J mice |agentStrain= Nine mile phase I |route= intraperitoneal |nDoses= 13 |doseUnits= PFU |response= death |bestFitModel=exponential|parameters=k =  5.7E-11 |N50= 1.22E+10 }}
{{DRSummaryTableEnd}}

=== '''<sup>*</sup>Recommended Model''' ===

It is recommended that experiment 28 should be used as the best dose-response model. A more virulent strain in experiment 28 can be more meaningful for emergency preparedness. Also, single host strain was used in experiment 28 instead of multiple strains as in experiment 26.

[[File:Exponential and betapoisson model.jpg|thumb|none|550px]]

=Experiment 28=

{{DRExperimentDataTable10|title=Mice/phase I Ohio strain model data|refer=Williams et al, 1982|reference=Williams JC and Cantrell JL (1982) Biological and immunological properties of Coxiella burnetii vaccines in C57BL/1OScN endotoxin-nonresponder mice. Infection and Immunity 35(3), 1091–1102.|pos=Dead|neg=Survived|d1=0.7|p1=0|n1=30|t1=30|d2=7|p2=0|n2=20|t2=20|d3=70|p3=0|n3=30|t3=30|d4=7000|p4=0|n4=30|t4=30|d5=7E+05|p5=0|n5=30|t5=30|d6=7E+06|p6=1|n6=19|t6=20|d7=7E+07|p7=6|n7=24|t7=30|d8=7E+08|p8=16|n8=14|t8=30|d9=7E+09|p9=23|n9=7|t9=30|d10=7E+10|p10=19|n10=1|t10=20}}


{{DRFit|title=Goodness of fit and model selection|devE=73.9|devB=1.11|delta=72.8|DFE=9|DFB=8|X2bPbetter=3.84|pbPbetter=0|X2GOFe=16.9|pGOFe=2.65e-12|X2GOFb=15.5|pGOFb=0.997|interpretation=Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.}}


{{DRConfidenceBetaPoisson|title=Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations|MLEa=3.57E-01|p5a=1.91E-01|p25a=2.20E-01|p50a=2.38E-01|p950a=6.34E-01|p975a=7.08E-01|p995a=9.84E-01|MLEN=4.93E+08|p5N=1.89E+08|p25N=2.41E+08|p50N=2.73E+08|p950N=9.34E+08|p975N=1.06E+09|p995N=1.36E+09}}


[[File:BPscatter ID28.png|thumb|left|500px|'''Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.''']][[File:BPmodel ID28.png|thumb|none|500px|'''beta Poisson model plot, with confidence bounds around optimized model''']]<br>


=Experiment 26=

{{DRExperimentDataTable13|title=Mice/Nine mile phase I model data|refer = Scott et al, 1987|reference=Scott, G. and J. C. Williams (1987). "[http://mic.sgmjournals.org/cgi/content/abstract/133/3/691 Pathological responses of inbred mice to phase I Coxiella Burnetii.]" Journal of General Microbiology '''133'''(3): 691–700.|pos=Dead|neg=Survived|d1=0.05|p1=0|n1=10|t1=10|d2=0.5|p2=0|n2=10|t2=10|d3=5|p3=0|n3=10|t3=10|d4=50|p4=0|n4=10|t4=10|d5=501|p5=0|n5=10|t5=10|d6=5010|p6=0|n6=10|t6=10|d7=50100|p7=0|n7=10|t7=10|d8=501000|p8=0|n8=10|t8=10|d9=5010000|p9=0|n9=10|t9=10|d10=5.01E+07|p10=0|n10=10|t10=10|d11=5.01E+08|p11=1|n11=9|t11=10|d12=5.01E+09|p12=3|n12=7|t12=10|d13=5.01E+10|p13=9|n13=1|t13=10}}


{{DRFit|title=Goodness of fit and model selection|devE=1.63|devB=0.693|delta=0.936|DFE=12|DFB=11|X2bPbetter=3.84|pbPbetter=0.333|X2GOFe=21|pGOFe=1|X2GOFb=19.7|pGOFb=1|interpretation=Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.}}


{{DRConfidenceExponential|title=Optimized k parameter for the exponential model, from 10000 bootstrap iterations|MLEk=5.7E-11|p5k=2.31E-11|p25k=2.94E-11|p50k=3.33E-11|p950k=1.38E-10|p975k=1.61E-10|p995k=2.13E-10|N50type=ID50/LD50/ETC|MLEN=1.22E+10|p5N=3.25E+09|p25N=4.30E+09|p50N=5.02E+09|p950N=2.08E+10|p975N=2.36E+10|p995N=2.99E+10}}


[[File:ExpHisto ID26.png|thumb|left|500px|'''Parameter histogram for exponential model (uncertainty of the parameter)''']][[File:ExpModel ID26.png|thumb|none|500px|'''Exponential model plot, with confidence bounds around optimized model''']]<br>

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===References===

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[[Category:Completed Dose Response Models: Bacteria]][[Category:Dose Response Model]][[Category:Coxiella burnetii]]