View source for Rickettsia rickettsi: Dose Response Models

==<center>'''''Rickettsia rickettsii'''''</center>==

<center><big>'''(Rocky Mountain spotted Fever)'''</big></center>

<center><big>'''Authors: Mark H. Weir and Sushil Tamrakar'''</big></center>


==='''Overview: ''Rickettsia rickettsi and Spotted Fever'''===

Rocky Mountain spotted fever is a disease endemic to North America is caused by ''Rickettsia rickettsi''. The bacterium is delivered to the victim by a tick bite, and is the most lethal disease of all Rickettsial illnesses, especially in the United States. While the main vector for the disease is via an insect (most typically a tick), there has been evidence cited in Saslaw and Carlisle (1966) that aerosol dissemination and infection can be possible as well. This form of exposure to the bacterium can still develop into the lethal form of the disease, therefore, aerosol animal models were needed. 

Typically rocky mountain spotted fever (RMSF) can be a misnomer, as the disease neither originated from this area of America and Canada, nor is it isolated to just this region or these countries. As the bacterium has been known to cause RMSF in south and central America as well. RMSF presents with sudden onset of flu-like symptoms, followed by the onset of a spotty rash, similar to pox, yet not raised above the skin as a pox is. Patients often require hospitalization from infection and can be fatal is not treated immediately and aggressively. 


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==='''Summary Data'''===

Saslaw and Carlisle in 1966 studied the aerosol infectivity of R. rickettsii in monkeys.  Rhesus monkeys were challenged with aerosolized pathogens and morbidity as well as mortality was observed (Saslaw and Carlisle 1966). Dupont et al. carried out a study of R. rickettsii (Sheila Smith) in human volunteers via the intradermal route(Dupont, Hornick et al. 1973). Sammons et al. exposed Macaca mulatta (Rhesus monkey) to R. rickettsii (strain Sheila Smith) via different routes to find the changes in blood serum constituents(Sammons, Kenyon et al. 1976).


{{DRSummaryTableStart|agent=''Rickettsia rickettsi''}}
{{DRSummaryTablePreferredModel|expID= 300 and 301 |refer=Saslaw and Carlisle 1966 and Dupont, Hornick et al. 1973|reference=Saslaw, S. and Carlisle, H.N. (1966) Aerosol Infection of Monkeys with ''Rickettsia Rickettsi.'' ''Bacteriological Reviews'' '''30'''(3): 636-644 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378256/pdf/bactrev00060-0166.pdf Full text and Dupont HL, Hornick RB, Dawkins AT, Heiner GG, Fabrikan.Ib, Wisseman CL and Woodward TE (1973) Rocky Mountain Spotted Fever - Comparative Study of  Active  Immunity Induced by Inactivated and Viable Pathogenic Rickettsia ricketsii. Journal of Infectious Diseases 128(3), 340-344. |host= Pooled data |agentStrain= R1 and Sheila Smith |route= NA |nDoses= 27 |doseUnits= CFU |response= morbidity |bestFitModel=beta-Poisson|parameters=&alpha;=  7.77E-01 , N<sub>50</sub> =  2.13E+01 |N50= 2.13E+01 }}
{{DRSummaryTableNonpreferredModel|expID= 300|refer=Saslaw and Carlisle 1966|reference=Saslaw, S. and Carlisle, H.N. (1966) Aerosol Infection of Monkeys with ''Rickettsia Rickettsi.'' ''Bacteriological Reviews'' '''30'''(3): 636-644 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378256/pdf/bactrev00060-0166.pdf Full text|host= Rhesus monkeys |agentStrain= R1 |route= aerosol |nDoses= 24 |doseUnits= CFU |response= morbidity |bestFitModel=beta-Poisson|parameters=&alpha;=  8.58E-01 , N<sub>50</sub> =  1.88E+01 |N50= 1.88E+01 }}
{{DRSummaryTableNonpreferredModel|expID= 301 |refer=Dupont, Hornick et al. 1973|reference=Dupont HL, Hornick RB, Dawkins AT, Heiner GG, Fabrikan.Ib, Wisseman CL and Woodward TE (1973) Rocky Mountain Spotted Fever - Comparative Study of  Active  Immunity Induced by Inactivated and Viable Pathogenic Rickettsia ricketsii. Journal of Infectious Diseases 128(3), 340-344.|host= Human  |agentStrain= Sheila Smith |route= intradermal  |nDoses= 3 |doseUnits= CFU  |response= clinical signs |bestFitModel=beta-Poisson|parameters=&alpha;=  6.75E-01 , N<sub>50</sub> =  2.36E+01 |N50= 2.36E+01 }}
{{DRSummaryTableNonpreferredModel|expID= 244 |refer=Saslaw and Carlisle, (1966) |reference=Saslaw, S. and Carlisle, H.N. (1966) Aerosol Infection of Monkeys with ''Rickettsia Rickettsi.'' ''Bacteriological Reviews'' '''30'''(3): 636-644 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378256/pdf/bactrev00060-0166.pdf Full text]|host= Rhesus monkey|agentStrain= NA |route= aerosol|nDoses= 24 |doseUnits= CFU |response= death |bestFitModel=beta-Poisson|parameters=&alpha;=  1.45E-01 , N<sub>50</sub> =  5.01E+01|N50= 5.01E+01 }}
{{DRSummaryNonpreferredModel|expID= 245 |refer=Sammons et al., (1976)|reference=Sammons, L.S., Kenyon, R.H. and Pedersen, C.E. Jr. (1976) Effect of Vaccination Schedule on Immune Response of ''Macca mulata'' to Cell Culture-Grown Rock Mountain Spotted Fever Vaccine. ''Journal of Clinical Microbiology'' '''4'''(3): 253-257|host= C57BL6 mice |agentStrain= KHW|route= intravenous|nDoses= 5 |doseUnits= CFU|response= infection |bestFitModel=exponential|parameters=k =  3.18E-03|N50= 2.18E+02 }}
{{DRSummaryTableEnd}}

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

The pooled model of human exposed intradermally and aerosol exposed rhesus monkey is the recommended model. Intradermal route is the one of the natural routes of infection and aerosol route might be an accidental or intentional route. Moreover, the experiment 301 was conducted with human volunteers.



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


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==='''Optimization Output for experiment 300 (''Rickettsia rickettsi'')'''===


{{DRExperimentDataTable24|title=Rhesus monkey Data|reference=Saslaw, S. and Carlisle, H.N. (1966) Aerosol Infection of Monkeys with ''Rickettsia Rickettsi.'' ''Bacteriological Reviews'' '''30'''(3): 636-644 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378256/pdf/bactrev00060-0166.pdf Full text]|pos=MORBIDITY|neg=NOT MORBIDITY|d1=25|p1=1|n1=3|t1=4|d2=66|p2=2|n2=0|t2=2|d3=83|p3=2|n3=0|t3=2|d4=99|p4=2|n4=0|t4=2|d5=182|p5=7|n5=0|t5=7|d6=1110|p6=1|n6=1|t6=2|d7=1770|p7=2|n7=0|t7=2|d8=2290|p8=2|n8=0|t8=2|d9=2590|p9=2|n9=0|t9=2|d10=3170|p10=2|n10=0|t10=2|d11=5060|p11=7|n11=0|t11=7|d12=5520|p12=2|n12=0|t12=2|d13=5650|p13=2|n13=0|t13=2|d14=5670|p14=1|n14=0|t14=1|d15=7460|p15=2|n15=0|t15=2|d16=9200|p16=2|n16=0|t16=2|d17=10800|p17=2|n17=0|t17=2|d18=16800|p18=2|n18=0|t18=2|d19=41000|p19=2|n19=0|t19=2|d20=45500|p20=3|n20=0|t20=3|d21=53200|p21=2|n21=0|t21=2|d22=55200|p22=2|n22=0|t22=2|d23=132000|p23=2|n23=0|t23=2|d24=149000|p24=2|n24=0|t24=2}}



{{DRFit|title=Goodness of fit and model selection|devE=27.6|devB=11.2|delta=16.4|DFE=23|DFB=22|X2bPbetter=3.84|pbPbetter=5.12e-05|X2GOFe=35.2|pGOFe=0.232|X2GOFb=33.9|pGOFb=0.972|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=8.58E-01|p5a=9.77E-04|p25a=9.77E-04|p50a=9.78E-04|p950a=5.70E+06|p975a=1.41E+08|p995a=1.62E+11|MLEN=1.88E+01|p5N=3.58E-01|p25N=1.81E+00|p50N=7.74E+00|p950N=1.02E+03|p975N=4.02E+03|p995N=3.71E+04}}


[[File:BPscatter ID300.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 ID300.png|thumb|none|500px|'''beta Poisson model plot, with confidence bounds around optimized model''']]<br>



==='''Optimization Output for experiment 301 (''Rickettsia rickettsi'')'''===

{{DRExperimentDataTable3|title=Human data( ''Rickettsia rickettsii'')|reference=Dupont, Hornick et al. 1973|reference=Dupont HL, Hornick RB, Dawkins AT, Heiner GG, Fabrikan.Ib, Wisseman CL and Woodward TE (1973) Rocky Mountain Spotted Fever - Comparative Study of  Active  Immunity Induced by Inactivated and Viable Pathogenic Rickettsia ricketsii. Journal of Infectious Diseases 128(3), 340-344.|pos=CLINICAL SIGNS|neg=NOT CLINICAL SIGNS|d1=13|p1=2|n1=4|t1=6|d2=126|p2=6|n2=1|t2=7|d3=1260|p3=17|n3=1|t3=18}}


{{DRFit|title=Goodness of fit and model selection|devE=13.5|devB=0.248|delta=13.2|DFE=2|DFB=1|X2bPbetter=3.84|pbPbetter=0.000277|X2GOFe=5.99|pGOFe=0.00119|X2GOFb=3.84|pGOFb=0.618|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=6.75E-01|p5a=1.17E-01|p25a=2.44E-01|p50a=3.31E-01|p950a=1.21E+03|p975a=3.74E+03|p995a=4.98E+03|MLEN=2.36E+01|p5N=2.56E-02|p25N=3.35E+00|p50N=7.30E+00|p950N=6.41E+01|p975N=8.91E+01|p995N=1.28E+02}}


[[File:BPscatter ID301.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 ID301.png|thumb|none|500px|'''beta Poisson model plot, with confidence bounds around optimized model''']]<br>



==='''Optimization Output for experiment 300 and 3001 (''Rickettsia rickettsi'')'''===


{{DRExperimentDataTable27|title=Pooled data (experiment no. 300 and 301)|reference=Pooled|pos=MORBIDITY|neg=NOT MORBIDITY|d1=13|p1=2|n1=4|t1=6|d2=25|p2=1|n2=3|t2=4|d3=66|p3=2|n3=0|t3=2|d4=83|p4=2|n4=0|t4=2|d5=99|p5=2|n5=0|t5=2|d6=126|p6=6|n6=1|t6=7|d7=182|p7=7|n7=0|t7=7|d8=1110|p8=1|n8=1|t8=2|d9=1260|p9=17|n9=1|t9=18|d10=1770|p10=2|n10=0|t10=2|d11=2290|p11=2|n11=0|t11=2|d12=2590|p12=2|n12=0|t12=2|d13=3170|p13=2|n13=0|t13=2|d14=5060|p14=7|n14=0|t14=7|d15=5520|p15=2|n15=0|t15=2|d16=5650|p16=2|n16=0|t16=2|d17=5670|p17=1|n17=0|t17=1|d18=7460|p18=2|n18=0|t18=2|d19=9200|p19=2|n19=0|t19=2|d20=10800|p20=2|n20=0|t20=2|d21=16800|p21=2|n21=0|t21=2|d22=41000|p22=2|n22=0|t22=2|d23=45500|p23=3|n23=0|t23=3|d24=53200|p24=2|n24=0|t24=2|d25=55200|p25=2|n25=0|t25=2|d26=132000|p26=2|n26=0|t26=2|d27=149000|p27=2|n27=0|t27=2}}



{{DRFit|title=Goodness of fit and model selection|devE=42.2|devB=11.7|delta=30.5|DFE=26|DFB=25|X2bPbetter=3.84|pbPbetter=3.41e-08|X2GOFe=38.9|pGOFe=0.0235|X2GOFb=37.7|pGOFb=0.989|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=7.77E-01|p5a=3.82E-01|p25a=4.41E-01|p50a=4.90E-01|p950a=4.24E+00|p975a=3.59E+03|p995a=3.25E+04|MLEN=2.13E+01|p5N=5.70E+00|p25N=8.34E+00|p50N=1.01E+01|p950N=4.00E+01|p975N=4.16E+01|p995N=5.10E+01}}


[[File:BPscatter ID300 301.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 ID300 301.png|thumb|none|500px|'''beta Poisson model plot, with confidence bounds around optimized model''']]<br>




==='''Optimization Output for experiment 244 (''Rickettsia rickettsi'')'''===

{{DRExperimentDataTable24|title=Rhesus monkey Data|refer=Saslaw and Carlisle, (1966) |reference=Saslaw, S. and Carlisle, H.N. (1966) Aerosol Infection of Monkeys with ''Rickettsia Rickettsi.'' ''Bacteriological Reviews'' '''30'''(3): 636-644 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378256/pdf/bactrev00060-0166.pdf Full text]|pos=Dead|neg=Survived|d1=25|p1=1|n1=3|t1=4|d2=66|p2=2|n2=0|t2=2|d3=83|p3=2|n3=0|t3=2|d4=99|p4=1|n4=1|t4=2|d5=182|p5=3|n5=4|t5=7|d6=1111|p6=1|n6=1|t6=2|d7=1774|p7=1|n7=1|t7=2|d8=2287|p8=1|n8=1|t8=2|d9=2586|p9=2|n9=0|t9=2|d10=3166|p10=1|n10=1|t10=2|d11=5055|p11=6|n11=1|t11=7|d12=5519|p12=2|n12=0|t12=2|d13=5652|p13=2|n13=0|t13=2|d14=5669|p14=1|n14=0|t14=1|d15=7459|p15=2|n15=0|t15=2|d16=9199|p16=1|n16=1|t16=2|d17=10774|p17=2|n17=0|t17=2|d18=16790|p18=1|n18=1|t18=2|d19=41023|p19=2|n19=0|t19=2|d20=45498|p20=1|n20=2|t20=3|d21=53206|p21=2|n21=0|t21=2|d22=55195|p22=2|n22=0|t22=2|d23=131771|p23=1|n23=1|t23=2|d24=149175|p24=2|n24=0|t24=2}}


{{DRFit|title=Goodness of fit and model selection|devE=137|devB=24|delta=113|DFE=23|DFB=22|X2bPbetter=3.84|pbPbetter=0|X2GOFe=35.2|pGOFe=0|X2GOFb=33.9|pGOFb=0.345|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=1.45E-01|p5a=1.82E-02|p25a=2.72E-02|p50a=4.15E-02|p950a=2.59E-01|p975a=2.87E-01|p995a=3.49E-01|MLEN=5.01E+01|p5N=6.71E-12|p25N=6.31E-07|p50N=2.86E-03|p950N=2.62E+02|p975N=3.28E+02|p995N=4.87E+02}}


[[File:BPscatter ID244.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 ID244.png|thumb|none|500px|'''beta Poisson model plot, with confidence bounds around optimized model''']]<br>


==='''Optimization Output for experiment 245'''===

{{DRExperimentDataTable5|title=C57BL/6 Mice KHW Strain Data|refer=Sammons et al., (1976)|reference=Sammons, L.S., Kenyon, R.H. and Pedersen, C.E. Jr. (1976) Effect of Vaccination Schedule on Immune Response of ''Macca mulata'' to Cell Culture-Grown Rock Mountain Spotted Fever Vaccine. ''Journal of Clinical Microbiology'' '''4'''(3): 253-257|pos=Infected|neg=Non-infected|d1=5|p1=0|n1=3|t1=3|d2=45|p2=1|n2=5|t2=6|d3=450|p3=6|n3=2|t3=8|d4=4500|p4=7|n4=0|t4=7|d5=45000|p5=7|n5=0|t5=7}}


{{DRFit|title=Goodness of fit and model selection|devE=0.155|devB=0.135|delta=0.0201|DFE=4|DFB=3|X2bPbetter=3.84|pbPbetter=0.887|X2GOFe=9.49|pGOFe=0.997|X2GOFb=7.81|pGOFb=0.987|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=3.18E-03|p5k=1.05E-03|p25k=1.41E-03|p50k=1.63E-03|p950k=7.50E-03|p975k=7.54E-03|p995k=1.46E-02|N50type=ID50/LD50/ETC|MLEN=2.18E+02|p5N=4.74E+01|p25N=9.19E+01|p50N=9.25E+01|p950N=4.25E+02|p975N=4.91E+02|p995N=6.63E+02}}


[[File:ExpHisto ID245.png|thumb|left|500px|'''Parameter histogram for exponential model (uncertainty of the parameter)''']][[File:ExpModel ID245.png|thumb|none|500px|'''Exponential model plot, with confidence bounds around optimized model''']]<br>


===References===

<references />
Dupont HL, Hornick RB, Dawkins AT, Heiner GG, Fabrikan.Ib, Wisseman CL and Woodward TE (1973) Rocky Mountain Spotted Fever - Comparative Study of  Active  Immunity Induced by Inactivated and Viable Pathogenic ''Rickettsia ricketsii''. ''Journal of Infectious Diseases'' 128(3), 340-344.

Saslaw S and Carlisle HN (1966) Aerosol infection of monkeys with ''Rickettsia rickettsii''. ''Bacteriological Reviews'' 30(3), 636-645.

Sammons LS, Kenyon RH and Pedersen CE (1976) Effect of vaccination schedule on immune response of ''Macaca mulatta'' to cell culture-grown Rocky Mountain spotted fever vaccine. ''Journal of Clinical Microbiology'' 4(3), 253-257.

[[Category:Completed Dose Response Models: Bacteria]][[Category:Dose Response Model]][[Category:Rickettsia rickettsi]]