Difference between revisions of "Salmonella Typhi: Dose Response Models"

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==<center>'''Typhoid ''Salmonella'''''</center>==
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==<center>'''''Salmonella'' Typhi'''</center>==
  
 
<center>'''Kyle S. Enger'''</center>
 
<center>'''Kyle S. Enger'''</center>
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''Salmonella enterica,'' serovar Typhi (''S.'' Typhi for short, but formerly known as ''Salmonella typhi'' or ''Salmonella typhosa'') causes typhoid fever.<ref name="Crump and Mintz 2010">Crump JA, Mintz ED, 2010 Global trends in typhoid and paratyphoid Fever. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 50(2), pp.241-246. [http://cid.oxfordjournals.org/content/50/2/241.full.pdf+html Full text]</ref> Paratyphoid fever is a similar syndrome (but less common and less severe than typhoid fever) caused by ''Salmonella enterica,'' serovar Typhi (''S.'' Paratyphi).<ref name="Miliotis and Bier 2003">Miliotis MD, Bier J eds. (2003) International Handbook of Foodborne Pathogens, New York: M. Dekker.</ref> Typhoid and paratyphoid fevers are also jointly known as enteric fever.<ref name="Crump and Mintz 2010"></ref> Other ''Salmonella enterica'' serovars (e.g., Enteritidis, Typhimurium) cause a gastroenteritis known as salmonellosis. <ref name="Miliotis and Bier 2003"></ref>
 
''Salmonella enterica,'' serovar Typhi (''S.'' Typhi for short, but formerly known as ''Salmonella typhi'' or ''Salmonella typhosa'') causes typhoid fever.<ref name="Crump and Mintz 2010">Crump JA, Mintz ED, 2010 Global trends in typhoid and paratyphoid Fever. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 50(2), pp.241-246. [http://cid.oxfordjournals.org/content/50/2/241.full.pdf+html Full text]</ref> Paratyphoid fever is a similar syndrome (but less common and less severe than typhoid fever) caused by ''Salmonella enterica,'' serovar Typhi (''S.'' Paratyphi).<ref name="Miliotis and Bier 2003">Miliotis MD, Bier J eds. (2003) International Handbook of Foodborne Pathogens, New York: M. Dekker.</ref> Typhoid and paratyphoid fevers are also jointly known as enteric fever.<ref name="Crump and Mintz 2010"></ref> Other ''Salmonella enterica'' serovars (e.g., Enteritidis, Typhimurium) cause a gastroenteritis known as salmonellosis. <ref name="Miliotis and Bier 2003"></ref>
  
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''S.'' Typhi and ''S.'' Paratyphi only infect humans and are transmitted by the fecal-oral route.<ref name="Miliotis and Bier 2003"></ref> Disease may include any combination of the following: cough, constipation, diarrhea, abdominal pain, anorexia, rose spots on the torso, or fever.<ref name="Miliotis and Bier 2003"></ref> ''S.'' Typhi may also be shed asymptomatically for years in the feces of chronic carriers. <ref name="Miliotis and Bier 2003"></ref>
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''S.'' Typhi and ''S.'' Paratyphi only infect humans and are transmitted by the fecal-oral route (Miliotis and Bier 2003). Disease may include any combination of the following: cough, constipation, diarrhea, abdominal pain, anorexia, rose spots on the torso, or fever (Miliotis and Bier 2003).  ''S.'' Typhi may also be shed asymptomatically for years in the feces of chronic carriers (Miliotis and Bier 2003).
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http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/
  
  
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----
 
  
 
==='''Summary of data'''===
 
==='''Summary of data'''===
  
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There have been two feeding studies<ref name="Hornick et al. (1966)">Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.</ref><ref name="Hornick et al. (1970)">Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]</ref> in male prisoners of the Quailes strain of ''S. ''Typhi (which was named ''Salmonella typhosa'' at that time). Data from these two studies can be pooled (P > 0.05), and the beta-Poisson model is superior to the exponential model for all datasets. Although the pooled model fails the goodness-of-fit test, it does not fail by much (P = 0.032), and therefore it is the preferred model.  
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There have been two feeding studies<ref name="Hornick et al. (1966)">Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.</ref><ref name="Hornick et al. (1970)">Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]</ref> in male prisoners of the Quailes strain of ''S. ''Typhi (which was named ''Salmonella typhosa'' at that time).  
  
 
Other model fits to these data have been published (Haas, Rose, and Gerba 1999). However, these model fits exclude some of the experimental data for unclear reasons.
 
Other model fits to these data have been published (Haas, Rose, and Gerba 1999). However, these model fits exclude some of the experimental data for unclear reasons.
  
  
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{{DRSummaryTableStart|agent=typhoid ''Salmonella''}}
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{{DRSummaryTableStart|agent=typhoid ''Salmonella Typhi''}}
 
{{DRSummaryPreferredModelmanyrefs|expID= 79, 80 |refer1=Hornick et al. (1966)|reference1= Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.|refer2=Hornick et al. (1970)|reference2= Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|host= human |agentStrain= Quailes |route= oral, in milk |nDoses= 8 |doseUnits= CFU |response= disease |bestFitModel=beta-Poisson|parameters=&alpha; =  1.75E-01 , N<sub>50</sub> =  1.11E+06|N50= 1.11E+06 }}
 
{{DRSummaryPreferredModelmanyrefs|expID= 79, 80 |refer1=Hornick et al. (1966)|reference1= Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.|refer2=Hornick et al. (1970)|reference2= Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|host= human |agentStrain= Quailes |route= oral, in milk |nDoses= 8 |doseUnits= CFU |response= disease |bestFitModel=beta-Poisson|parameters=&alpha; =  1.75E-01 , N<sub>50</sub> =  1.11E+06|N50= 1.11E+06 }}
 
{{DRSummaryTableNonpreferredModel|expID= 79 |refer = Hornick et al. (1966)|reference=Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.|host= human |agentStrain= Quailes |route= oral, in milk |nDoses= 3 |doseUnits= CFU |response= disease |bestFitModel=beta-Poisson|parameters=&alpha; =  1.11E-01 , N<sub>50</sub> =  3.45E+06|N50= 3.45E+06 }}"
 
{{DRSummaryTableNonpreferredModel|expID= 79 |refer = Hornick et al. (1966)|reference=Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.|host= human |agentStrain= Quailes |route= oral, in milk |nDoses= 3 |doseUnits= CFU |response= disease |bestFitModel=beta-Poisson|parameters=&alpha; =  1.11E-01 , N<sub>50</sub> =  3.45E+06|N50= 3.45E+06 }}"
 
{{DRSummaryTableNonpreferredModel|expID= 80 |refer =Hornick et al. (1970) |reference=Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|host= human |agentStrain= Quailes |route= oral, in milk |nDoses= 5 |doseUnits= CFU |response= disease |bestFitModel=beta-Poisson|parameters=&alpha; =  2.03E-01 , N<sub>50</sub> =  8.53E+05|N50= 8.53E+05 }}
 
{{DRSummaryTableNonpreferredModel|expID= 80 |refer =Hornick et al. (1970) |reference=Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|host= human |agentStrain= Quailes |route= oral, in milk |nDoses= 5 |doseUnits= CFU |response= disease |bestFitModel=beta-Poisson|parameters=&alpha; =  2.03E-01 , N<sub>50</sub> =  8.53E+05|N50= 8.53E+05 }}
 
{{DRSummaryTableEnd}}
 
{{DRSummaryTableEnd}}
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==<sup>*</sup>Recommended Model==
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The pooled model of experiment number 79 and 80 is the recommended model. Pooling is statistically accepted and it gives improvement in fits.
  
  
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==='''Optimization Output for experiment 79, 80'''===
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==='''Optimization Output for experiment 79, 80 (''Salmonella'' Typhi)'''===
  
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{{DRExperimentDataTable8manyrefs|title=Model data for S. Typhi (Quailes) in humans |refer1=Hornick et al. (1966)|reference1= Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.|refer2=Hornick et al. (1970)|reference2= Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|pos=Disease|neg=No disease|d1=1000|p1=0|n1=14|t1=14|d2=1E+05|p2=28|n2=76|t2=104|d3=1E+05|p3=32|n3=84|t3=116|d4=1E+07|p4=15|n4=15|t4=30|d5=1E+07|p5=16|n5=16|t5=32|d6=1E+08|p6=8|n6=1|t6=9|d7=1E+09|p7=4|n7=0|t7=4|d8=1E+09|p8=40|n8=2|t8=42}}
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{{DRExperimentDataTable8manyrefs|title=Model data for ''S.'' Typhi (Quailes) in humans |refer1=Hornick et al. (1966)|reference1= Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.|refer2=Hornick et al. (1970)|reference2= Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|pos=Disease|neg=No disease|d1=1000|p1=0|n1=14|t1=14|d2=1E+05|p2=28|n2=76|t2=104|d3=1E+05|p3=32|n3=84|t3=116|d4=1E+07|p4=15|n4=15|t4=30|d5=1E+07|p5=16|n5=16|t5=32|d6=1E+08|p6=8|n6=1|t6=9|d7=1E+09|p7=4|n7=0|t7=4|d8=1E+09|p8=40|n8=2|t8=42}}
  
  
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==='''Optimization Output for experiment 79'''===
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==='''Optimization Output for experiment 79 (''Salmonella'' Typhi)'''===
  
 
{{DRExperimentDataTable3|title=Model data for ''S.'' Typhi (Quailes) in humans|refer = Hornick et al. (1966)|reference=Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.
 
{{DRExperimentDataTable3|title=Model data for ''S.'' Typhi (Quailes) in humans|refer = Hornick et al. (1966)|reference=Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.
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==='''Optimization Output for experiment 80'''===
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==='''Optimization Output for experiment 80 (''Salmonella'' Typhi)'''===
  
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{{DRExperimentDataTable5|title=Model data for S. Typhi (Quailes) in humans |refer =Hornick et al. (1970) |reference=Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|pos=Disease|neg=No disease|d1=1000|p1=0|n1=14|t1=14|d2=1E+05|p2=32|n2=84|t2=116|d3=1E+07|p3=16|n3=16|t3=32|d4=1E+08|p4=8|n4=1|t4=9|d5=1E+09|p5=40|n5=2|t5=42}}
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{{DRExperimentDataTable5|title=Model data for ''S.'' Typhi (Quailes) in humans |refer =Hornick et al. (1970) |reference=Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. [http://www.nejm.org/doi/pdf/10.1056/NEJM197010012831406 Abstract]|pos=Disease|neg=No disease|d1=1000|p1=0|n1=14|t1=14|d2=1E+05|p2=32|n2=84|t2=116|d3=1E+07|p3=16|n3=16|t3=32|d4=1E+08|p4=8|n4=1|t4=9|d5=1E+09|p5=40|n5=2|t5=42}}
  
  
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<references />
 
<references />
 +
Crump JA and Mintz ED (2010) Global Trends in Typhoid and Paratyphoid Fever. ''Clinical Infectious Diseases'' 50(2), 241-246.
 +
 +
Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT and Snyder MJ (1970) Typhoid Fever: Pathogenesis and Immunologic Control. ''New England Journal of Medicine'' 283(13), 686-691.
 +
 +
Hornick RB, Woodward TE, McCrumb FR, Snyder MJ, Dawkins AT, Bulkeley JT, De la Macorra F and Corozza FA (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. ''Transactions of the Association of American Physicians'' 79, 361-367.
 +
 +
Miliotis MD and Bier JW (2003) ''International Handbook of Foodborne Pathogens''. New York, Marcel Dekker. Inc.
  
  

Latest revision as of 15:47, 15 February 2013

Salmonella Typhi

Kyle S. Enger


Overview

Salmonella enterica, serovar Typhi (S. Typhi for short, but formerly known as Salmonella typhi or Salmonella typhosa) causes typhoid fever.[1] Paratyphoid fever is a similar syndrome (but less common and less severe than typhoid fever) caused by Salmonella enterica, serovar Typhi (S. Paratyphi).[2] Typhoid and paratyphoid fevers are also jointly known as enteric fever.[1] Other Salmonella enterica serovars (e.g., Enteritidis, Typhimurium) cause a gastroenteritis known as salmonellosis. [2]

S. Typhi and S. Paratyphi only infect humans and are transmitted by the fecal-oral route (Miliotis and Bier 2003). Disease may include any combination of the following: cough, constipation, diarrhea, abdominal pain, anorexia, rose spots on the torso, or fever (Miliotis and Bier 2003). S. Typhi may also be shed asymptomatically for years in the feces of chronic carriers (Miliotis and Bier 2003).


http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/


Summary of data

There have been two feeding studies[3][4] in male prisoners of the Quailes strain of S. Typhi (which was named Salmonella typhosa at that time).

Other model fits to these data have been published (Haas, Rose, and Gerba 1999). However, these model fits exclude some of the experimental data for unclear reasons.


Experiment serial number Reference Host type Agent strain Route # of doses Dose units Response Best fit model Optimized parameter(s) LD50/ID50
79, 80* [3][4] human Quailes oral, in milk 8 CFU disease beta-Poisson α = 1.75E-01 , N50 = 1.11E+06 1.11E+06
79 [3] human Quailes oral, in milk 3 CFU disease beta-Poisson α = 1.11E-01 , N50 = 3.45E+06 3.45E+06"
80 [4] human Quailes oral, in milk 5 CFU disease beta-Poisson α = 2.03E-01 , N50 = 8.53E+05 8.53E+05
*This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.


*Recommended Model

The pooled model of experiment number 79 and 80 is the recommended model. Pooling is statistically accepted and it gives improvement in fits.


Exponential and betapoisson model.jpg

Optimization Output for experiment 79, 80 (Salmonella Typhi)

Model data for S. Typhi (Quailes) in humans [3][4]
Dose Disease No disease Total
1000 0 14 14
1E+05 28 76 104
1E+05 32 84 116
1E+07 15 15 30
1E+07 16 16 32
1E+08 8 1 9
1E+09 4 0 4
1E+09 40 2 42


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom		 χ20.95,1
p-value		 χ20.95,m-k
p-value
Exponential 419 406 7 3.84
0 		14.1
0
Beta Poisson 13.8 6 12.6
0.0321
Neither the exponential nor beta-Poisson fits well; beta-Poisson is less bad.


Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.75E-01 1.21E-01 1.32E-01 1.39E-01 2.23E-01 2.34E-01 2.58E-01
N50 1.11E+06 5.13E+05 6.10E+05 6.72E+05 2.00E+06 2.28E+06 2.95E+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


Optimization Output for experiment 79 (Salmonella Typhi)

Model data for S. Typhi (Quailes) in humans [3]
Dose Disease No disease Total
1E+05 28 76 104
1E+07 15 15 30
1E+09 4 0 4


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom		 χ20.95,1
p-value		 χ20.95,m-k
p-value
Exponential 124 121 2 3.84
0 		5.99
0
Beta Poisson 2.87 1 3.84
0.0905
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
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.11E-01 3.19E-02 4.80E-02 5.49E-02 1.96E-01 2.17E-01 2.59E-01
N50 3.45E+06 4.81E+05 6.95E+05 8.50E+05 9.53E+07 2.24E+08 4.19E+09


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


Optimization Output for experiment 80 (Salmonella Typhi)

Model data for S. Typhi (Quailes) in humans [4]
Dose Disease No disease Total
1000 0 14 14
1E+05 32 84 116
1E+07 16 16 32
1E+08 8 1 9
1E+09 40 2 42


Goodness of fit and model selection
Model Deviance Δ Degrees
of freedom		 χ20.95,1
p-value		 χ20.95,m-k
p-value
Exponential 293 284 4 3.84
0 		9.49
0
Beta Poisson 8.63 3 7.81
0.0346
Neither the exponential nor beta-Poisson fits well; beta-Poisson is less bad.


Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 2.03E-01 1.33E-01 1.49E-01 1.57E-01 2.74E-01 2.89E-01 3.27E-01
N50 8.53E+05 3.38E+05 4.28E+05 4.80E+05 1.62E+06 1.85E+06 2.49E+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


References

  1. ↑ 1.0 1.1 Crump JA, Mintz ED, 2010 Global trends in typhoid and paratyphoid Fever. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 50(2), pp.241-246. Full text
  2. ↑ 2.0 2.1 Miliotis MD, Bier J eds. (2003) International Handbook of Foodborne Pathogens, New York: M. Dekker.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Hornick RB, et al. (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians. 79, pp.361-367.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Hornick RB, et al. (1970) Typhoid fever: pathogenesis and immunologic control. The New England Journal of Medicine. 283(13), pp.686-691. Abstract

Crump JA and Mintz ED (2010) Global Trends in Typhoid and Paratyphoid Fever. Clinical Infectious Diseases 50(2), 241-246.

Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT and Snyder MJ (1970) Typhoid Fever: Pathogenesis and Immunologic Control. New England Journal of Medicine 283(13), 686-691.

Hornick RB, Woodward TE, McCrumb FR, Snyder MJ, Dawkins AT, Bulkeley JT, De la Macorra F and Corozza FA (1966) Study of induced typhoid fever in man. I. Evaluation of vaccine effectiveness. Transactions of the Association of American Physicians 79, 361-367.

Miliotis MD and Bier JW (2003) International Handbook of Foodborne Pathogens. New York, Marcel Dekker. Inc.

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