Difference between revisions of "Enteroviruses: Dose Response Models"

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<center><big>'''Author: Yin Huang'''</big></center>
 
<center><big>'''Author: Yin Huang'''</big></center>
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<center>'''If you want to download this chapter in pdf format, please click [http://wiki.camra.msu.edu/images/b/b8/Enterovirus.pdf here]''' </center>
 
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<center>'''If you want to download the excel spreadsheet of tables, please click the captions of tables.  If you want to download a specific figure, just click on the figure'''</center>
 
  
  
 
==='''General overview '''===
 
==='''General overview '''===
  
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Enterovirus, a kind of small (30 nm), nonenveloped, single-stranded RNA viruses, belongs to the family ''Picornaviridae''. While most of the enterovirus infections are relatively mild and result in complete recovery of the patient, they can also cause severe and fatal diseases such as meningitis, encephalitis, myocarditis, neonatal sepsis, and polio. Infection occurs mainly via fecal-oral transmission and less commonly by respiratory droplets. While no known non-human reservoirs have been identified, water-borne, foodborne, and blood-borne transmissions have been reported (Stalkup and Chilukuri 2002).
+
Enterovirus, a small (30 nm), nonenveloped, single-stranded RNA viruses, belongs to the family ''Picornaviridae''. While most of the enterovirus infections are relatively mild and result in complete recovery of the patient, they can also cause severe and fatal diseases such as meningitis, encephalitis, myocarditis, neonatal sepsis, and polio like paralytic diseases. Infection occurs mainly via fecal-oral transmission and less commonly by respiratory droplets. While no known non-human reservoirs have been identified, water-borne, foodborne, and blood-borne transmissions have been reported (Stalkup and Chilukuri 2002).
  
  
 
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==='''Summary Data'''===
 
==='''Summary Data'''===
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Cliver (1981) challenged pigs with Porcine enterovirus type 3 and 7 via oral exposure route.
 
Cliver (1981) challenged pigs with Porcine enterovirus type 3 and 7 via oral exposure route.
  
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{|
 
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ '''Table 3.1. Summary of the enterovirus data and best fits'''
 
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| Experiment number || Reference || Host type/pathogen strain || Route/number of doses || Dose units || Response || Best-fit model || Optimized parameters || LD<sub>50</sub>
 
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|-
 
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| 1 || Cliver, 1981 || pigs/ Porcine enterovirus type 3 || oral/3 || pfu || infection || Beta-Poisson || k=2.96E-04 || 2340.15
 
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|-
 
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| 2 || Cliver, 1981 || pigs/ Porcine enterovirus type 7 || oral/3 || pfu || infection || Beta-Poisson || k=3.75E-03 || 185.10
 
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|}
 
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|}
 
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'''The data from different experiments were not able to be statistically pooled.'''
 
  
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----
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{{DRSummaryTableStart|agent=Enteroviruses}}
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{{DRSummaryTablePreferredModel|expID= 63 |refer=Cliver, 1981|reference=Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection '''44''': 861-865.|host= pig |agentStrain= porcine, PE7-05i |route= oral |nDoses= 3 |doseUnits= PFU |response= infection |bestFitModel=exponential|parameters=k =  3.74E-03 |N50= 1.85E+02 }}
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{{DRSummaryNonpreferredModel|expID= 62 |refer=Cliver, 1981|reference=Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection '''44''': 861-865.|host= pig |agentStrain= porcine, PE3-ECPO-6 |route= oral  |nDoses= 3 |doseUnits= PFU |response= infection |bestFitModel=exponential|parameters=k =  2.96E-04 |N50= 2.34E+03 }}
 +
{{DRSummaryTableEnd}}
  
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==='''Optimized Models and Uncertainty and Fitting Analyses'''===
 
  
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'''Output for experiment 1.'''
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=== '''<sup>*</sup>Recommended Model''' ===
  
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{|
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It is recommended that experiment 63 should be used as the best dose-response model.
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ [http://wiki.camra.msu.edu/index.php?title=File:Cliver1981_Enterovirus_datafitconf_1.xls '''Table 20.2: Dose response data''']
 
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| Dose (pfu) || death || survival || Total
 
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|-
 
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| 1.00E+02 || 0 || 3 || 3
 
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|-
 
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| 2.50E+02 || 0 || 6 || 6
 
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|-
 
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| 1.00E+03 || 2 || 4 || 6
 
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|-
 
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| colspan = "4" | Cliver, 1981.
 
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|}
 
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|}
 
  
 +
[[File:Exponential and betapoisson model.jpg|thumb|none|550px]]
  
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{|
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----
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ [http://wiki.camra.msu.edu/index.php?title=File:Cliver1981_Enterovirus_datafitconf_1.xls '''Table 20.3: Goodness of fit and model selection''']
 
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| Model||Deviance||&Delta;||DF||&chi;<sup>2</sup><sub>0.95,df</sub>||&chi;<sup>2</sup><sub>0.95,1</sub>
 
−
|-
 
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| Exponential
 
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| 1.24
 
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| rowspan = "2" | 0
 
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| 2
 
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| 5.99
 
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| rowspan = "2" | 3.84
 
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|-
 
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| Beta Poisson<sup>*</sup>
 
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| 1.24
 
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| 1
 
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| 3.84
 
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|-
 
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| colspan = "6" | '''*Conclusion:  Both models fit well, but the exponential model is better than beta-Poisson.'''
 
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|}
 
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ [http://wiki.camra.msu.edu/index.php?title=File:Cliver1981_Enterovirus_datafitconf_1.xls '''Table 20.4: Parameters for the best-fit model (exponential ), obtained from 1E4 bootstrap iterations''']
 
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| rowspan = "2" | Parameter or value
 
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| rowspan = "2" | MLE Estimate
 
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| colspan = "6" | Percentiles
 
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|-
 
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| 0.50%||2.5%||5%||95%||97.5%||99.5%
 
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|-
 
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| k
 
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| 0.000296
 
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| 2.40E-17
 
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| 2.40E-17
 
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| 2.40E-17
 
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| 0.000719
 
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| 0.000719
 
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| 0.001025
 
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|-
 
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| LD<sub>50</sub> (spores)
 
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| 2340.15
 
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| 676.5683
 
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| 963.8791
 
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| 963.8791
 
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| 2.89E+16
 
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| 2.89E+16
 
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| 2.89E+16
 
−
|}
 
−
|}
 
  
 +
==='''Optimization Output for experiment 63'''===
  
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[[File:Cliver1981(1)_Enterovirus_ExpHist.png|thumb|left|500px|<center>'''(a)'''</center>]][[File:Cliver1981(1)_Enterovirus_ExpModel.png|thumb|none|500px|<center>'''(b)'''</center>]]
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{{DRExperimentDataTable3|title=pigs/ Porcine enterovirus type 7|refer=Cliver, 1981|reference=Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection '''44''': 861-865.|pos=infected|neg=Non-infected|d1=250|p1=4|n1=2|t1=6|d2=250|p2=3|n2=3|t2=6|d3=1000|p3=5|n3=0|t3=5}}
  
  
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'''Fig 20.1. Models plot for experiment 1. (a) Uncertainty plot of exponential model; (b) Plot of exponential model with upper and lower 95% and 99% confidence.'''
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{{DRFit|title=Goodness of fit and model selection|devE=0.614|devB=0.614|delta=-5.49e-05|DFE=2|DFB=1|X2bPbetter=3.84|pbPbetter=1|X2GOFe=5.99|pGOFe=0.736|X2GOFb=3.84|pGOFb=0.433|interpretation=Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.}}
  
  
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----
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{{DRConfidenceExponential|title=Optimized k parameter for the exponential model, from 10000 bootstrap iterations|MLEk=3.74E-03|p5k=1.83E-03|p25k=2.19E-03|p50k=2.19E-03|p950k=5.62E-03|p975k=5.62E-03|p995k=5.62E-03|N50type=ID50/LD50/ETC|MLEN=1.85E+02|p5N=1.23E+02|p25N=1.23E+02|p50N=1.23E+02|p950N=3.16E+02|p975N=3.16E+02|p995N=3.79E+02}}
  
  
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'''Output for experiment 2.'''
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[[File:ExpHisto ID63.png|thumb|left|500px|'''Parameter histogram for exponential model (uncertainty of the parameter)''']][[File:ExpModel ID63.png|thumb|none|500px|'''Exponential model plot, with confidence bounds around optimized model''']]<br>
  
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{|
 
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ [http://wiki.camra.msu.edu/index.php?title=File:Cliver1981_Enterovirus_datafitconf_2.xls '''Table 20.5: Dose response data''']
 
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| Dose (pfu) || death || survival || Total
 
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|-
 
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| 2.50E+02 || 4 || 2 || 6
 
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|-
 
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| 2.50E+02 || 3 || 3 || 6
 
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|-
 
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| 1.00E+03 || 5 || 0 || 5
 
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|-
 
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| colspan = "4" | Cliver, 1981.
 
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|}
 
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|}
 
  
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==='''Optimization Output for experiment 62'''===
  
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{|
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{{DRexperimentDataTable3|title=Pigs/ Porcine enterovirus type 3 Strain  model data|refer=Cliver, 1981|reference=Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection '''44''': 861-865.|pos=infected|neg=Non-infected |d1=100|p1=0|n1=3|t1=3|d2=250|p2=0|n2=6|t2=6|d3=1000|p3=2|n3=4|t3=6}}
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ [http://wiki.camra.msu.edu/index.php?title=File:Cliver1981_Enterovirus_datafitconf_2.xls '''Table 20.6: Goodness of fit and model selection''']
 
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| Model||Deviance||&Delta;||DF||&chi;<sup>2</sup><sub>0.95,df</sub>||&chi;<sup>2</sup><sub>0.95,1</sub>
 
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|-
 
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| Exponential
 
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| 0.61
 
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| rowspan = "2" | 0
 
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| 2
 
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| 5.99
 
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| rowspan = "2" | 3.84
 
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|-
 
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| Beta Poisson<sup>*</sup>
 
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| 0.61
 
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| 1
 
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| 3.84
 
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|-
 
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| colspan = "6" | '''*Conclusion:  Both models fit well, but the exponential model is better than beta-Poisson.'''
 
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|}
 
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| STYLE="vertical-align: top; text-align: center"|
 
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{| border = "1"
 
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|+ [http://wiki.camra.msu.edu/index.php?title=File:Cliver1981_Enterovirus_datafitconf_2.xls '''Table 20.7: Parameters for the best-fit model (exponential ), obtained from 1E4 bootstrap iterations''']
 
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| rowspan = "2" | Parameter or value
 
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| rowspan = "2" | MLE Estimate
 
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| colspan = "6" | Percentiles
 
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|-
 
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| 0.50%||2.5%||5%||95%||97.5%||99.5%
 
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|-
 
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| k
 
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| 0.0037
 
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| 0.001829
 
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| 0.002191
 
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| 0.002191
 
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| 0.005619
 
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| 0.005619
 
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| 0.005619
 
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|-
 
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| LD<sub>50</sub> (spores)
 
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| 185.10
 
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| 123.3551
 
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| 123.3551
 
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| 123.3551
 
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| 316.3171
 
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| 316.3171
 
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| 378.9585
 
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|}
 
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|}
 
  
  
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[[File:Cliver1981(2)_Enterovirus_ExpHist.png|thumb|left|500px|<center>'''(a)'''</center>]][[File:Cliver1981(2)_Enterovirus_ExpModel.png|thumb|none|500px|<center>'''(b)'''</center>]]
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{{DRFit|title=Goodness of fit and model selection|devE=1.24|devB=1.24|delta=-0.000314|DFE=2|DFB=1|X2bPbetter=3.84|pbPbetter=1|X2GOFe=5.99|pGOFe=0.537|X2GOFb=3.84|pGOFb=0.265|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=2.96E-04|p5k=2.40E-17|p25k=2.40E-17|p50k=2.40E-17|p950k=7.19E-04|p975k=7.19E-04|p995k=1.02E-03|N50type=ID50/LD50/ETC|MLEN=2.34E+03|p5N=6.77E+02|p25N=9.64E+02|p50N=9.64E+02|p950N=2.89E+16|p975N=2.89E+16|p995N=2.89E+16}}
  
  
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'''Fig 20.2. Models plot for experiment 2. (a) Uncertainty plot of exponential model; (b) Plot of exponential model with upper and lower 95% and 99% confidence.'''
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[[File:ExpHisto ID62.png|thumb|left|500px|'''Parameter histogram for exponential model (uncertainty of the parameter)''']][[File:ExpModel ID62.png|thumb|none|500px|'''Exponential model plot, with confidence bounds around optimized model''']]<br>
  
  
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==='''Summary'''===
 
==='''Summary'''===
  
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The different LD<sub>50</sub> for these two experiments indicates various virulence between pathogen strains.
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The different LD<sub>50</sub> for these two experiments indicates that virulence varies between pathogen strains.
  
  
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==='''References'''===
 
==='''References'''===
 +
 +
<references />
  
 
Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection '''44''': 861-865.
 
Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection '''44''': 861-865.
  
 
Stalkup, J. R. and S. Chilukuri (2002). "[http://www.ncbi.nlm.nih.gov/pubmed/12120436 Enterovirus infections: a review of clinical presentation, diagnosis, and treatment.]" Dermatologic clinics '''20'''(2): 217-223.
 
Stalkup, J. R. and S. Chilukuri (2002). "[http://www.ncbi.nlm.nih.gov/pubmed/12120436 Enterovirus infections: a review of clinical presentation, diagnosis, and treatment.]" Dermatologic clinics '''20'''(2): 217-223.
 +
 +
 +
[[Category:Dose Response Model]][[Category:Virus]][[Category:Enteroviruses]]

Latest revision as of 17:07, 15 February 2013

Enteroviruses

Author: Yin Huang


General overview

Enterovirus, a small (30 nm), nonenveloped, single-stranded RNA viruses, belongs to the family Picornaviridae. While most of the enterovirus infections are relatively mild and result in complete recovery of the patient, they can also cause severe and fatal diseases such as meningitis, encephalitis, myocarditis, neonatal sepsis, and polio like paralytic diseases. Infection occurs mainly via fecal-oral transmission and less commonly by respiratory droplets. While no known non-human reservoirs have been identified, water-borne, foodborne, and blood-borne transmissions have been reported (Stalkup and Chilukuri 2002).


Summary Data

Cliver (1981) challenged pigs with Porcine enterovirus type 3 and 7 via oral exposure route.


Experiment serial number Reference Host type Agent strain Route # of doses Dose units Response Best fit model Optimized parameter(s) LD50/ID50
63* [1] pig porcine, PE7-05i oral 3 PFU infection exponential k = 3.74E-03 1.85E+02
62 [1] pig porcine, PE3-ECPO-6 oral 3 PFU infection exponential k = 2.96E-04 2.34E+03
*This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.


*Recommended Model

It is recommended that experiment 63 should be used as the best dose-response model.

Exponential and betapoisson model.jpg

Optimization Output for experiment 63

pigs/ Porcine enterovirus type 7 [1]
Dose infected Non-infected Total
250 4 2 6
250 3 3 6
1000 5 0 5


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom		 χ20.95,1
p-value		 χ20.95,m-k
p-value
Exponential 0.614 -5.49e-05 2 3.84
1 		5.99
0.736
Beta Poisson 0.614 1 3.84
0.433
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 3.74E-03 1.83E-03 2.19E-03 2.19E-03 5.62E-03 5.62E-03 5.62E-03
ID50/LD50/ETC* 1.85E+02 1.23E+02 1.23E+02 1.23E+02 3.16E+02 3.16E+02 3.79E+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


Optimization Output for experiment 62

Pigs/ Porcine enterovirus type 3 Strain model data [1]
Dose infected Non-infected Total
100 0 3 3
250 0 6 6
1000 2 4 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 1.24 -0.000314 2 3.84
1 		5.99
0.537
Beta Poisson 1.24 1 3.84
0.265
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 2.96E-04 2.40E-17 2.40E-17 2.40E-17 7.19E-04 7.19E-04 1.02E-03
ID50/LD50/ETC* 2.34E+03 6.77E+02 9.64E+02 9.64E+02 2.89E+16 2.89E+16 2.89E+16
*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


Summary

The different LD50 for these two experiments indicates that virulence varies between pathogen strains.



References

  1. ↑ 1.0 1.1 1.2 1.3 Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection 44: 861-865.

Cliver, D. O. (1981). "Experimental infection by waterborne enteroviruses." Journal of Food Protection 44: 861-865.

Stalkup, J. R. and S. Chilukuri (2002). "Enterovirus infections: a review of clinical presentation, diagnosis, and treatment." Dermatologic clinics 20(2): 217-223.

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