Indian Science Cruiser, Vol. 27, No. 5, Special issue on Sir Ronald Ross.

Mathematical modeling of infectious disease

N.C. Ghosh* ABSTRACT Human suffers from infectious disease since prehistoric time. Some times epidemic infectious disease causes mass death toll. So attempts were been ta en to sa!e human ind from such infectious diseases. "ith the ad!ent of science branches of it are ha!e been associate with this endea!our. In recent #earsmathematical modelin$ has become a !aluable tool in the anal#sis of infectious disease d#namics and to support the de!elopment of control strate$ies.%athematical models can pro&ect how infectious diseases pro$ress to show the li el# outcome of an epidemic and help inform public health inter!entions. %odels use some basic assumptions and mathematics to find parameters for !arious infectious diseases and use those parameters to calculate the effects of possible inter!entions, li e mass !accination pro$rammes. Here author attempt to discuss basic problems from mathematical !iew. Introduction : It is not known when infectious diseases first started to attack human race; but like other animals man kind suffers from it from earl !eriod. There are some natural measures to !rotect animal" but men isolated from animal race are #ictim infectious diseases; some times in wide ran$. Attem!ts were been taken to sa#e mankind from infectious diseases and is continuin$ in modern era. %irstl mathematical conce!ts were been used to #isualise the !roblem in scientific manner andbut from last centur mathematicalideas are been used for man other anal tical as!ects of it. &athematical modelin$now are im!ortant tools to stud these !roblems.In recent ears understandin$ of infectious'disease e!idemiolo$ and control has been $reatl increased throu$h mathematical modelin$. Insi$hts from this increasin$l 'im!ortant" e(citin$ field are now informin$ !olic 'makin$ at the hi$hest le#els" and !la in$ a $rowin$ role in research. The transmissible nature of infectious diseases makes them fundamentall different from non' infectious diseases" so techni)ues from *classical* e!idemiolo$ are often in#alid and hence lead to incorrect conclusions ' not least in health'economic anal sis. So mathematical anal sis are not onl im!ortant to measure $ra#it of infectious diseases" its causal as!ects" !h siolo$ical as well clinical as!ects are also been taken care of. &athematical modelin$ now !la s a ke role in !olic makin$" includin$ health'economic as!ects; emer$enc !lannin$ and risk assessment; control'!ro$ramme e#aluation; and monitorin$ of sur#eillance data. In research" it is essential in stud desi$n" anal sis +includin$ !arameter estimation, and inter!retation. -arl !ioneers in infectious disease modelin$ were .illiam /amer and Ronald Ross" who in the earl twentieth centur a!!lied the law of mass action to e(!lain e!idemic beha#iour. 0owell Reed and .ade /am!ton %rost de#elo!ed the Reed1%rost e!idemic model to describe the relationshi! between susce!tible" infected and immune indi#iduals in a !o!ulation.2#er the last two decades" mathematical models ha#e seen a hu$e de#elo!ment in all as!ects of infectious diseases" from microbiolo$ to e!idemiolo$ and e#olution. In recent ears understandin$ of infectious'disease e!idemiolo$ and control has been $reatl increased throu$h

Dr. Narayan ChGhosh, Professor in Mathematics, having thirty seven years teaching and research experience in India and abroad. Email $hosnara#an'$mail.com, Mobile !" !#$""%%$&', !" !($$#)%)*%, !" !#%(&&$!(!, !" %$$ &*#%$'*$, !" %$$ &*#%&$*' mathematicalmodelin$. &artini" and 0otka has done a $ood 3ob on such modelin$. Startin$ in 4567 8ermack and &c8endrick !ublished !a!ers on e!idemic models and obtained the e!idemic threshold result that the densit of susce!tible must e(ceed a critical #alue in order for an e!idemic outbreak to occur. &athematical e!idemiolo$ seems to ha#e $rown e(!onentiall startin$ in the middle of the 69th centur +the :rst edition in 45;< of Baile =s book is an im!ortant landmark," so that a tremendous #ariet of models ha#e now been formulated" mathematicall anal >ed" and a!!lied to infectious diseases. Re#iews of the literature show the ra!id $rowth of e!idemiolo$ modelin$. As the transmissible nature of infectious diseases makes them fundamentall different from non'infectious diseases and conse)uence of which techni)ues from *classical* e!idemiolo$ are often in#alid as it leads to incorrect conclusions for health'economic anal sis and e#en to combat effect of diseases !rofessionals in these fields are now e(!osed to a wide ran$e of models. The recent models ha#e in#ol#ed as!ects such as !assi#e immunit " $radual loss of #accine and disease'ac)uired immunit " sta$es of infection" #ertical transmission" disease #ectors" macro!arasitic loads" a$e structure" social and se(ual mi(in$ $rou!s" s!atial s!read" #accination" )uarantine" and chemothera! . Mathematical Formulation : .ith infectious diseases fre)uentl dominatin$ news headlines" !ublic health and !harmaceutical industr !rofessionals" !olic makers" and infectious disease researchers" increasin$l need to understand the transmission !atterns of infectious diseases" to be able to inter!ret and criticall 'e#aluate both e!idemiolo$ical data" and the findin$s of mathematical modelin$ studies. Recentl there has been ra!id !ro$ress in de#elo!in$ models and new techni)ues for measurement and anal sis" which ha#e been a!!lied to outbreaks and emer$in$ e!idemics. %or mathematical models it is essential to inte$rate the increasin$ #olume of data bein$ $enerated on host'!atho$en interactions. &an theoretical studies of the !o!ulation d namics" structure and e#olution of infectious diseases of !lants and animals" includin$ humans" are concerned with this !roblem. In such in#esti$ation Research to!ics include? a. Transmission" s!read and control of infection" b. -!idemiolo$ical networks" c. S!atial e!idemiolo$ " d. @ersistence of !atho$ens within hosts" e. Intra'host d namics" f. Immuno'e!idemiolo$ " $. Airulence" h. Strain +biolo$ , structure and interactions" i. Anti$enic shift" 3. @h lod namics" k. @atho$en !o!ulation $enetics" l.-#olution and s!read of resistance" m. Role of host $enetic factors" n. Statistical and mathematical tools and inno#ations" o. Role and identification of infection reser#oirs. Basic ideas for mathematical formulation de!ends on the conce!ts of i. @o!ulation d namics" ii. Beterministic and stochastic models" iii. Network anal sis" i#. .ithin'host d namics of #iral and bacterial infections" #. &athematical re#iew +calculus" !robabilities...," #i. A!!lied !ro$rammin$ with R" #ii. Statistical modelin$" #iii. Com!uter'based simulations &odels are onl as $ood as the assum!tions on which the are based. If a model makes !redictions which are out of line with obser#ed results and the mathematics is correct" the initial assum!tions must chan$e to make the model useful. Rectan$ular a$e distribution is often well'3ustified for de#elo!ed countries where there is a low infant
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mortalit and much of the !o!ulation li#es to the life e( other New Corkers" and within New Cork then there will be smaller sub$rou!s such as the African communit or teena$ers +3ust to $i#e two e(am!les, who will mi( with each other more than !eo!le outside their $rou!. /owe#er" homo$eneous mi(in$ is a standard assum!tion to make the mathematics tractable.2n the other hand for homo$eneous mi(in$ of the !o!ulation" i.e." indi#iduals of the !o!ulation under scrutin assort and make contact at random and do not mi( mostl in a smaller sub$rou!" this assum!tion is rarel 3ustified because social structure is wides!read" for e(am!le" most !eo!le in New Cork" onl make contact with contact with other New Corkers" and within New Cork. In realit most of the societies now are of hetero$eneous character. Therefore for mathematical model number of !arameters increases to dealt with and then it becomes com!le(. &athematical models are bein$ increasin$l used to elucidate the transmission of infections and to e#aluate the !otential im!act of control !ro$rammes in reducin$ morbidit and mortalit . A!!lications include determinin$ o!timal control strate$ies a$ainst new infections and !redictin$ the im!act of #accination strate$ies a$ainst common infections. Recentl there has been ra!id !ro$ress in de#elo!in$ models and new techni)ues for measurement and anal sis" which ha#e been a!!lied to outbreaks and emer$in$ e!idemics" such as SARS" a#ian influen>a or !andemic influen>a. A sim!le but !owerful new techni)ue for assessin$ the !otential of different methods to control an infectious'disease outbreak was recentl de#elo!ed. Dto know more one ma see at the site ? htt!?EEwww.eid.ed.ac.ukEe#entEintroduction'mathematical'models'e!idemiolo$ 'control' infectious'diseases'im!erial'colle$eFlonGsthash.@d<HI&cT.d!uf J. Infectious Disease Dynamics &athematical models need to inte$rate the increasin$ #olume of data bein$ $enerated on host'!atho$en interactions. &an theoretical studies of the !o!ulation d namics" structure and e#olution of infectious diseases of !lants and animals" includin$ humans" are concerned with this !roblem. Research to!ics include? a. Transmission " s!read and control of infection" b.-!idemiolo$ical networks" c. S!atial e!idemiolo$ " c. @ersistence of !atho$ens within hosts" d. Intra'host d namics" e. Immuno'e!idemiolo$ " f. Airulencem $" Strain +biolo$ , structure and interactions" h. Anti$enic shift " i. @h lod namics " 3. @atho$en !o!ulation $enetics" k. -#olution and s!read of resistance" l. Role of host $enetic factors" m. Statistical and mathematical tools and inno#ations" n. Role and identification of infection reser#oirs Endemic Steady State An infectious disease is said to be endemic when it can be sustained in a !o!ulation without the need for e(ternal in!uts. This means that" on a#era$e" each infected !erson is infectin$ e(actl# one other !erson +an more and the number of !eo!le infected will $row e(!onentiall and there will be an e!idemic" an less and the disease will die out,. In mathematical terms" that is? R) KS F 4. .here the basic re!roduction number +R9, of the disease" assumin$ e#er one is susce!tible" S the !ro!ortion of the !o!ulation who are susce!tible to the disease +neither immune nor infected. @roduct of R9 andSmust be one +since those who are not susce!tible do not feature in our calculations as the cannot contract the disease,. Notice that this relation means that for a disease to be in the endemic stead state" the hi$her the basic re!roduction
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number" the lower the !ro!ortion of the !o!ulation susce!tible must be" and #ice #ersa.%or abo#e cited first assum!tion +abo#e, lets us sa that e#er one in the !o!ulation li#es to a$e * and then dies. If the a#era$e a$e of infection is +" then on a#era$e indi#iduals oun$er then + are susce!tible and those older than + are immune +or infectious,. Thus the !ro!ortion of the !o!ulation that is susce!tible is $i#en b

But the mathematical definition of the endemic stead state can be rearran$ed to $i#e? Therefore" This !ro#ides a sim!le wa to estimate the !arameter R9 usin$ easil a#ailable data. %or a !o!ulation with an e(!onential a$e distribution" This allows for the basic re!roduction number of a disease $i#en + and * in either t !e of !o!ulation distribution. Mathematics of mass vaccination If the !ro!ortion of the !o!ulation that is immune e(ceeds the herd immunit le#el for the disease" then the disease can no lon$er !ersist in the !o!ulation. The infectious disease can be eliminated if herd immunit le#el can be e(ceeded b #accination. An e(am!le of this bein$ successfull achie#ed worldwide is the $lobal eradication of small!o(" with the last wild case in 45<<. The ./2 is carr in$ out a similar #accination cam!ai$n to eradicate !olio. The herd immunit le#el will be denoted ,. 2ne to recall that" for a stable state? S will be +4 L ,," since , is the !ro!ortion of the !o!ulation that is immune and , M S must e)ual to one +since in this sim!lified model" e#er one is either susce!tible or immune,. Then?

This is the threshold le#el. If the !ro!ortion of immune indi#iduals e(ceeds this le#el due to a mass #accination !ro$ramme" the disease will sa die out. /ere the critical immunisation threshold +denoted ,c, 3ust calculated. It is the minimum !ro!ortion of the !o!ulation that must be immunised at birth +or close to birth, in order for the infection to die out in the !o!ulation. If the #accine used is insufficientl effecti#e or the re)uired co#era$e cannot be reached +for e(am!le due to !o!ular resistance and or some other factors," the !ro$ramme ma fail to e(ceed ,c. Such a !ro$ramme can" howe#er" disturb the balance of the infection without eliminatin$ it" often causin$ unforeseen !roblems. Su!!ose that a !ro!ortion of the !o!ulation , +where , N,c, is immunised at birth a$ainst an infection with R9O4. The #accination !ro$ramme chan$es R9 to R, where
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This chan$e occurs sim!l because there are now fewer susce!tible in the !o!ulation who can be infected. R, is sim!l R) minus those that would normall be infected but that cannot be now since the are immune. As a conse)uence of this lower basic re!roduction number" the a#era$e a$e of infection + will also chan$e to some new #alue +)inthose who ha#e been left un#accinated. /ere one can recall the relation that linked R 9" + and *. Assumin$ that life e(!ectanc has not chan$ed" now?

But R9 F *E+ so? The #accination !ro$ramme will raise the a#era$e a$e of infection" another mathematical 3ustification for a result that mi$ht ha#e been intuiti#el ob#ious. Pn#accinated indi#iduals now e(!erience a reduced force of infection due to the !resence of the #accinated $rou!. When mass vaccination exceeds the herd immunity If a #accination !ro$ramme causes the !ro!ortion of immune indi#iduals in a !o!ulation to e(ceed the critical threshold for a si$nificant len$th of time" transmission of the infectious disease in that !o!ulation will sto!. This is known as elimination of the infection and is different from eradication. Elimination Interru!tion of endemic transmission of an infectious disease" which occurs if each infected indi#idual infects less than one other" is achie#ed b maintainin$ #accination co#era$e to kee! the !ro!ortion of immune indi#iduals abo#e the critical immunisation threshold. Eradication Reduction of infecti#e or$anisms in the wild worldwide to >ero. So far" this has onl been achie#ed for small!o( and rinder!est. To $et to eradication" elimination in all world re$ions must be achie#ed. Essential to be careful for Studying epidemic infectious disease :-!idemiolo$ists deal with man uncontrollable" inde!endent #ariables usin$ ad#anced statistical techni)ues and carefull desi$ned e(!eriments. %orStud in$ such Besi$nsone need be careful on followin$ tools A. Aariables 4. Be!endent #ariable 1 the outcome #ariable ' -(am!les +in e!idemiolo$ ,? Risk of de#elo!in$ a disease" se#erit of disease" inde( associated with disease such as e3ection fraction +fraction of blood enterin$ the heart that is e3ected out in one beat, 6. Inde!endent #ariables 1 the #ariables ou mani!ulate" measure" andEor record ' -(am!les? A$e" $ender" Q bod fat" amount of !h sical acti#it I. -(traneous #ariables 1 #ariables not measured or controlled" assumed to ha#e no relation to the outcome #ariable or to be accounted for b randomi>ation ' -(am!le? - e color" number of siblin$s B. Correlation #ersus Causalit 4. A correlation is a $reater than nothin$ relationshi! between two #ariables
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6. Correlation does N2T necessitate causalit ' Cows lie down before it rains ' In the 69th Centur " the murder rate rose and the shee! farmin$ rate fell ' Smokin$ causes lun$ cancer" or is it factor KR I. Correlation is measured usin$ SrT or SR6T ' r ran$es from 14 to 4 ' R6 ran$es from 9 to 4 C. -(!erimental Besi$n 4. -(!erimental studies in#ol#e the mani!ulation of one or more inde!endent #ariables ' -(am!le? A clinical trial for a treatment 1 dru$" er$o$enic aid" or e(ercise e.$. ' -(am!le? Bietar mani!ulation such as low fat or low C/2" hot or cold en#ironment" Q o( $en in air 6. &ore than two cate$ories of an inde!endent #ariable are called Sle#elsT ' e.$." hi$h intensit " moderate intensit " low intensit " or no e(ercise I. -(!erimental studies are intended to establish mechanisms ' causalit B. -(!erimental and Control Grou!s 4. -(!erimental studies randoml assi$n sub3ects to either an e(!erimental or a control $rou! 6. The e(!erimental $rou!+s, recei#e+s, the inter#ention 1 the IA of interest 1 a s!ecial diet" a dru$" or an e(ercise !ro$ram I. The control $rou! is as identical as !ossible to the e(!erimental $rou! in e#er facet -KC-@T the inde!endent #ariable of interest 1 no s!ecial diet" no dru$" no e(ercise !ro$ram U. @otential confounders +#ariables that could affect the BA, are ho!efull balanced between the two +or more, $rou!s -. Bias control 4. -(!erimental studies are susce!tible to both sub3ect and e(!erimental bias ' A sub3ect who thinks that creatine +e.$., will make him +or her, stron$er ma unconsciousl tr harder durin$ testin$ after su!!lementation than before ' @lacebo effect ' An e(!erimenter who e(!ects a dru$ to im!ro#e s m!toms ma unconsciousl rate s m!toms as more se#ere without the dru$ than with the dru$ 6. To control for these effects" e(!eriments can be a. Blind 1 the sub3ect does not know which $rou! he or she is in 1 the e(!erimental or control $rou! b. Bouble'blind 1 neither the sub3ect nor the e(!erimenter knows which $rou! the sub3ect is in %. 2bser#ational Stud Besi$ns 4. 2bser#ational studies do not in#ol#e direct mani!ulation of a #ariable" althou$h sub3ects ma be $rou!ed accordin$ to the le#el of a #ariable" e.$. has disease or does not" a$e $rou!" hi$hEmediumElow !h sical acti#it le#el, V Cross'sectional V Retros!ecti#e +case'control, V @ros!ecti#e +lon$itudinal, 6. Cross'Sectional ' Indi#iduals are selected at random from a !o!ulation and both the IA=s and the
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BA=s are measured in all sub3ects at one time ' This stud desi$n allows correlations to be made between !otential risk factors +such as inacti#it , and disease ' %or e(am!le" is SmalenessT related to a hi$her incidence of creatinesu!!lementation amon$ athletesR ' This stud desi$n does not allow causalit to be established I. Retros!ecti#e ' Also called case'control desi$n ' Sub3ects are di#ided accordin$ to an outcome #ariable +has diseaseEdoes not ha#e disease, and the IA=s are measured retros!ecti#el 1 accordin$ to medical records" etc. ' Recall is susce!tible to error and bias ' A$ain" allows correlations to be established" but not causalit U. 0on$itudinal ' Also called !ros!ecti#e desi$n ' Initiall health indi#iduals are tested and retested" for both IA=s and BA=s o#er time ' -.G? &uscle stren$th in !eo!le who do and do not en$a$e in resistance e(ercise measured at a$e U9" ;9" and 79 ' Bifficult to retain all sub3ects due to chan$in$ interests W a#ailabilit " mo#in$" mortalit etc. ' 0ooks for IA=s with !ower to !redict the BA" e.$." smokin$ !redicts more than H9Q of lun$ cancer cases ' Stud can establish correlation but not causalit If in#esti$ator desire he can ado!t !robabilistic a!!roach also considerin$ case series. ase series Case'series ma refer to the )ualitati#e stud of the e(!erience of a sin$le !atient" or small $rou! of !atients with a similar dia$nosis" or to a statistical techni)ue com!arin$ !eriods durin$ which !atients are e(!osed to some factor with the !otential to !roduce illness with !eriods when the are une(!osed.The former t !e of stud is !urel descri!ti#e and cannot be used to make inferences about the $eneral !o!ulation of !atients with that disease. These t !es of studies" in which an astute clinician identifies an unusual feature of a disease or a !atient*s histor " ma lead to formulation of a new h !othesis. Psin$ the data from the series" anal tic studies could be done to in#esti$ate !ossible causal factors. These can include case control studies or !ros!ecti#e studies. A case control stud would in#ol#e matchin$ com!arable controls without the disease to the cases in the series. A !ros!ecti#e stud would in#ol#e followin$ the case series o#er time to e#aluate the disease*s natural histor . The latter t !e" more formall described as self'controlled case'series studies" di#ide indi#idual !atient follow'u! time into e(!osed and une(!osed !eriods and use fi(ed'effects @oisson re$ression !rocesses to com!are the incidence rate of a $i#en outcome between e(!osed and une(!osed !eriods. This techni)ue has been e(tensi#el used in the stud of ad#erse reactions to #accination" and has been shown in some circumstances to !ro#ide statistical !ower com!arable to that a#ailable in cohort studies. ase control studies

Case control studies select sub3ects based on their disease status. A $rou! of indi#iduals that are disease !ositi#e +the XcaseX $rou!, is com!ared with a $rou! of disease ne$ati#e indi#iduals +the XcontrolX $rou!,. The control $rou! should ideall come from the same !o!ulation that $a#e rise to the cases. The case control stud looks back throu$h time at !otential e(!osures that both $rou!s +cases and controls, ma ha#e encountered. A table of 6Y6 !attern is been constructed" dis!la in$ e(!osed cases +A," e(!osed controls +B," une(!osed cases +C, and une(!osed controls +B,. The statistic $enerated to measure association is the odds ratio +2R," which is the ratio of the odds of e(!osure in the cases +AEC, to the odds of e(!osure in the controls +BEB," i.e. 2R F +ABEBC, as !!!!! ontrols es -(!osed A B B

Pne(!osed C

If the 2R is clearl $reater than 4" then the conclusion is Xthose with the disease are more likel to ha#e been e(!osed"X whereas if it is close to 4 then the e(!osure and disease are not likel associated. But if the 2R is far less than one" then this su$$ests that the e(!osure is a !rotecti#e factor in the causation of the disease. Case control studies are usuall faster and more cost effecti#e than cohort studies" but are sensiti#e to bias +such as recall bias and selection bias,. The main challen$e is to identif the a!!ro!riate control $rou!; the distribution of e(!osure amon$ the control $rou! should be re!resentati#e of the distribution in the !o!ulation that $a#e rise to the cases. This can be achie#ed b drawin$ a random sam!le from the ori$inal !o!ulation at risk. This has as a conse)uence that the control $rou! can contain !eo!le with the disease under stud when the disease has a hi$h attack rate in a !o!ulation. A ma3or drawback for such case control studies is that" in order to be considered to be statisticall si$nificant" the minimum number of cases re)uired at the 5;Q confidence inter#al is related to the odds ratio b the e)uation? Total cases F +aMc, F +4.57,Z6Y+4MN,Y+4[ln+2R,,Z6Y++2RM6\2RM4,[\2R, ]4;.;Y+4MN,Y+4[ln+2R,,Z6 where N F The ratio of cases to controls. As the odds ratio a!!roached 4" a!!roaches 9; renderin$ case control studies all but useless for low odds ratios. %or instance" for an odds ratio of 4.; and cases F controls" the table shown abo#e would look like this? as !!!!! ontrols es -(!osed 49I
8

HU

Pne(!osed %or an odds ratio of 4.4? !!!!! -(!osed Pne(!osed

HU ases 4<I6 47;6

49I ontrols 47;6 4<I6

ohort studies Cohort studies select sub3ects based on their e(!osure status. The stud sub3ects should be at risk of the outcome under in#esti$ation at the be$innin$ of the cohort stud ; this usuall means that the should be disease free when the cohort stud starts. The cohort is followed throu$h time to assess their later outcome status. The same 6Y6 table is constructed as with the case control stud . /owe#er" the !oint estimate $enerated is the relati#e risk +RR," which is the !robabilit of disease for a !erson in the e(!osed $rou!" -e F + E ++ M ., o#er the !robabilit of disease for a !erson in the une(!osed $rou!" -u F C E +C M /," i.e. RR F -e E -u. a "on# !!!!! $otal se case -(!osed + . ++ M ., Pne(!osed C / +C M / , As with the 2R" a RR $reater than 4" shows association" where the conclusion can be read Xthose with the e(!osure were more likel to de#elo! disease. @ros!ecti#e studies ha#e man benefits o#er case control studies. The RR is a more !owerful effect measure than the 2R" as the 2R is 3ust an estimation of the RR" since true incidence cannot be calculated in a case control stud where sub3ects are selected based on disease status. Tem!oralit can be established in a !ros!ecti#e stud " and confounders are more easil controlled for. /owe#er" the are more costl " and there is a $reater chance of losin$ sub3ects to follow'u! based on the lon$ time !eriod o#er which the cohort is followed. Cohort studies also are limited b the same e)uation for number of cases as for cohort studies" but" if the base incidence rate in the stud !o!ulation is #er low" the number of cases re)uired is reduced b ^. %utbrea& investigation 'alidity: precision and bias Bifferent fields in e!idemiolo$ ha#e different le#els of #alidit . 2ne wa to assess the #alidit of findin$s is the ratio of false'!ositi#es +claimed effects that are not correct, to false' ne$ati#es +studies which fail to su!!ort a true effect,. To take the field off $enetic e!idemiolo$ " candidate'$ene studies !roduced o#er 499 false'!ositi#e findin$s for each false'ne$ati#e. B contrast $enome'wide association a!!ears close to the re#erse" with onl one false !ositi#e for e#er 499 or more false'ne$ati#es.This ratio has im!ro#ed o#er time in $enetic e!idemiolo$ as the field has ado!ted strin$ent criteria. In contrast other e!idemiolo$ical fields ha#e not re)uired such ri$orous re!ortin$ and are much less reliable as a result. Random error Random error is the result of fluctuations around a true #alue because of sam!lin$ #ariabilit . It is error 3ust that random. It can occur durin$ data collection" codin$" transfer" or anal sis. -(am!les of random error include? !oorl worded )uestions" a misunderstandin$ in inter!retin$ an indi#idual answer from a !articular res!ondent" or a t !o$ra!hical error durin$
9

codin$. Random error affects measurement in a transient" inconsistent manner and it is im!ossible to correct for random error. Sampling error There is random error in all sam!lin$ !rocedures which is called sampling error.@recision in e!idemiolo$ical #ariables is a measure of random error. @recision is also in#ersel related to random error" so that to reduce random error is to increase !recision. Confidence inter#als are com!uted to demonstrate the !recision of relati#e risk estimates. The narrower the confidence inter#al" the more !recise the relati#e risk estimate. To reduce random error in an epidemiological studythere are two basic wa s. The first is to increase the sam!le si>e of the stud . In other words" add more sub3ects to our stud . The second is to reduce the #ariabilit in measurement in the stud . This mi$ht be accom!lished b usin$ a more !recise measurin$ de#ice or b increasin$ the number of measurements. Systematic error A s stematic error or bias occurs when there is a difference between the true #alue +in the !o!ulation, and the obser#ed #alue +in the stud , from an cause other than sam!lin$ #ariabilit . An e(am!le of s stematic error is if" unknown to in#esti$ator" the pulse oximeter he is usin$ is set incorrectl and adds two !oints to the true #alue each time a measurement is taken. The measurin$ de#ice could be precise but not accurate. Because the error ha!!ens in e#er instance" it is s stematic. Then conclusions drawn based on that data will still be incorrect. But the error can be re!roduced in the future +e.$." b usin$ the same mis'set instrument,. A mistake in codin$ that affects all res!onses for that !articular )uestion is another e(am!le of a s stematic error. The #alidit of a stud is de!endent on the de$ree of s stematic error. Aalidit is usuall se!arated into two com!onents? Internal validity is de!endent on the amount of error in measurements" includin$ e(!osure" disease" and the associations between these #ariables. Good internal #alidit im!lies a lack of error in measurement and su$$ests that inferences ma be drawn at least as the !ertain to the sub3ects under stud . External validity !ertains to the !rocess of $enerali>in$ the findin$s of the stud to the !o!ulation from which the sam!le was drawn +or e#en be ond that !o!ulation to a more uni#ersal statement,. This re)uires an understandin$ of which conditions are rele#ant +or irrele#ant, to the $enerali>ation. Internal #alidit is clearl a !rere)uisite for e(ternal #alidit . (t the end of discussion it is necessary to note that biasness can threaten the validity of a study! So no discussion on &athematical modelin$ of infectious disease is com!lete with out sa in$ an thin$ on Bias. $hree are three types of bias:i! Selection bias) ii! Information bias) and iii! onfounding Selection bias :Selection bias occurs when stud sub3ects are selected or become !art of the stud as a result of a third" unmeasured #ariable which is associated with both the e(!osure and outcome of interest. Information bias :It is bias arisin$ from s stematic error in the assessment of a #ariable.An e(am!le of this is recall bias. onfounding : onfounding has traditionall been defined as bias arisin$ from the co' occurrence or mi(in$ of effects of e(traneous factors" referred to as confounders" with the main effect+s, of interest.A more recent definition of confoundin$ in#okes the notion of counterfactual effects. Accordin$ to this #iew" when one obser#es an outcome of
10

interest" sa CF4 +as o!!osed to CF9," in a $i#en !o!ulation A which is entirel e(!osed +i.e. e(!osure 0 F 4 for e#er unit of the !o!ulation, the risk of this e#ent will be RA4. The counterfactual or unobser#ed risk RA9 corres!onds to the risk which would ha#e been obser#ed if these same indi#iduals had been une(!osed +i.e. 0 F 9 for e#er unit of the !o!ulation,. The true effect of e(!osure therefore is? RA4 L RA9 +if one is interested in risk differences, or RA4ERA9 +if one is interested in relati#e risk,. Since the counterfactual risk RA9 is unobser#able one has to a!!ro(imate it usin$ a second !o!ulation B and can measure usin$ followin$ relations?RA4 L RB9 or RA4ERB9. In this situation" confoundin$ occurs when RA9 _ RB9. +NB? -(am!le assumes binar outcome and e(!osure #ariables., Some of the e!idemiolo$ists !refer to think confoundin$ se!aratel from common cate$ori>ations of bias since" unlike selection and information bias" confoundin$ stems from real causal effects. Ross#MacDonald model +oss,s - Priori Pathometry and Mathematical Epidemiology Ross*s malaria models alone would ha#e earned him a !lace in histor " but he was also instrumental in establishin$ the intellectual foundations for the stud of disease d namics. But Ross was not the first to model an infectious disease; se#eral earl !a!ers had alread established the foundations of e!idemiolo$ . In the ear 4H;; `ohn Snow had !ublished the classical stud of cholera and se#eral )uantitati#e" but mainl statistical" studies in e!idemiolo$ followed Snow at the end if the 45th centur . Ross*s mathematical ideas also had !recursors. In the ear 4<79 Baniel Bernoulli de#elo!ed a d namic model of small!o( transmission and control" a remarkable stud of disease transmission d namics had been !ublished b -n*ko in Russian in 4HH5 and /amer !ublished a measles transmission model in 4597. Ross*s as!irations were not 3ust to understand malaria" but also to establish a new branch of science. In 459H" when he !ublished his first d namic model of malaria" Ross coined the !hrase S a priori!athometr T to describe the scientific acti#it of modelin$ transmission d namics" and in the ear 4544" he !resented a new set of e)uations as !art of a $eneral framework. Ross*s second malaria model was a s!ecial case of his new" $eneral theor ? he called malaria a Smeta(enousT disease. In 454;" he sol#ed the $eneral e)uations" and discussed his work in relation to Brownlee*s" who was de#elo!in$ a com!lementar set of methods for stud in$ e!idemics. Both Ross and Brownlee used the terms a priori and a posteriori to describe two different a!!roaches to stud in$ e!idemics" thou$h the switched the meanin$s. In the ear 4547" Ross !ublished the first of a three'!art series !a!ers la in$ out the e(!anded theor of a priori !athometr . Ross described the priori method" Swe assume a nowled$e of the causes, construct our differential e,uations on that supposition, follow up the lo$ical conse,uences, and finall# test the calculated results b# comparin$ them with the obser!ed statistics,1 and the a posteriorimethod" 2we commence with obser!ed statistics, endea!our to fit anal#tical laws to them, and so wor bac wards to the underl#in$ cause 3as done in much statistical wor of the da#4.1 Ross ar$ued that e!idemics were" per se" a !henomenon worth of stud . Ross belie#ed that the stud of e!idemics was intrinsicall )uantitati#e and that e!idemics were e(tremel com!licated" so understandin$ them would re)uire a combination of mathematical modelin$ based on a priori notions of cause and e(amination of !atterns in data throu$h statistical in#esti$ation. The last two !arts of his series !a!ers were /ilda /udson was and were !ublished in the ear 454<. In 456<" 8ermack and &c8endrick !ublished the first of their seminal !a!ers; &c8endrick had been with Ross in Sierra 0eone" and his work acknowled$es the contributions of Ross and /udson. Ross called the
11

field Sa priori !athometr T" or Sconstructi#e e!idemiolo$ T " but it is now more widel known as mathematical e!idemiolo$ . Se#eral )uantities are commonl defined as !art of the Ross'&acdonald model; the !o!ulation densit of humans" H; the !o!ulation densit of mos)uitoes" %; the number of infected humans" 0; the number of infected" but not et infectious mos)uitoes" 5; the number of infectious mos)uitoes" 6; the human blood feedin$ rate" the !ro!ortion of mos)uitoes that feed on humans each da " a; mos)uito sur#i#al as either the !robabilit of sur#i#in$ one da " p" or the instantaneous death rate" $ +p 7 e8$ or $ F Lln p,; the !atho$ens* #ertebrate latent !eriod" often called the Sintrinsic incubation !eriodT" the number of da s from infection to infectiousness in the human" u; the !atho$en*s mos)uito latent !eriod" often called the Se(trinsic incubation !eriodT" the number of da s from infection to infectiousness in the mos)uito" !; the dail rate each human reco#ers from infection" r; the !ro!ortion of infected humans that are infectious" or alternati#el " the !robabilit a mos)uito becomes infected after bitin$ an infected human" c; and the !ro!ortion of bites b infectious mos)uitoes that infect a human" b. It is also sometimes useful to consider the human blood feedin$ rate as the !roduct of a blood feedin$ rate" f" and the fraction of blood meals on humans" or more $enerall " the !atho$en*s host" 9 3a 7 f94. So these Im!ortant and measurable )uantities need be reco$ni>ed in models includin$? the !re#alence of malaria" malaria rate" or !arasite rate + ( 7 0:H,; the fraction of infected but not infectious +# 7 5:%, or infectious mos)uitoes +; 7 6:%,; the ratio of mos)uitoes to humans + m 7 %:H,; the number of bites b #ectors !er human !er da " called the human bitin$ rate +/BR" ma," the number of infectious bites !er human !er da " called the entomolo$ical inoculation rate +-IR" ma; or < in e)uations,; the force of infection or Sha!!enin$sT rate for human infections +h 7 mab;,; the a#era$e lifes!an of a mos)uito +=:$," the number of human bites !er mos)uito o#er its lifes!an" called the stabilit inde( +SI" a:$ or S in e)uations,; the !robabilit an infected mos)uito sur#i#es to become infections +- 7 e8$!,; the a#era$e number of da s a !erson remains infected +=:r," the net infectiousness of humans to mos)uitoes" the !robabilit a mos)uito becomes infected after feedin$ on a human + > 7 c(," the force of infection or Sha!!enin$sT rate for mos)uito infections +a>,. %ormulas are $i#en in the main te(t for the #ectorial ca!acit +V, or dail re!roducti#e number and basic re!roducti#e number + R), and the critical densit of mos)uitoes re)uired for sustainin$ transmission +m?,. -ach #ersion of the Ross'&acdonald model has used a subset of these !arameters" but each one has also utili>ed a different notation. $he Ross#Waite#*ot&a Model Ross*s first d namic model of malaria was further de#elo!ed b .aite and0otka. 0otka wrote the model more ele$antl as a sim!le difference e)uation? Ross formulated a )uantit " " is #er similar to #ectorial ca!acit . The deri#ation is #er similar" but there are some differences. Ross*s time ste! was one month" and his formula considered at most two bites !er mos)uito each month" one that infected it and one that transmitted the !arasites. Thus" in the ali$nment of notation" the inter!retation of Ross*s f +or e)ui#alentl bp, is not identical to the human blood feedin$ rate" a. .aite*s time ste! was the inter#al between bites" but he retained the inter!retation of f. $he Ross#*ot&a Model
12

The second d namic model of malaria was !ublished b Ross twice in 4544" first as an addendum to the second edition of @he -re!ention of %alaria" and then in Nature. 2ne ear later" 0otka !ro!osed a closed'form solution" and in the ear 456I 0otka thorou$hl anal >ed it. The model formulation was more focused on mathematical details" and not on the entomolo$ical ones. The !arameters here ha#e been su!!lied from ali$nment ?

It must be noted that Ross also considered births and deaths in both the human and #ector !o!ulations" but he set these e)ual to each other so the !o!ulations would be in their stead state for anal sis. .he /harpe01ot2a Model Shar!e and 0otka e(tended Ross*s model to consider the latent !eriod in both humans and mos)uitoes?

The anal sis is focused on mathematical details" not biolo$ical ones" and so the model ne$lects mos)uito mortalit durin$ the latent !eriod and therefore the conclude that the dela has no effect on the e)uilibrium. Macdonald) Ir+in) Diet,) and Superinfection &acdonald*s com!lete model was !resented in a series of !a!ers and e(ce!t for the ori$inal !a!er on su!erinfection" usuall rele$ated to brief summaries in the a!!endices of his !a!ers. The model he uses is essentiall the followin$ The Sha!!enin$sT rate is defined b the formula?

&acdonald and Irwin first defined a function describin$ the reco#er rate under su!erinfection. The mathematical model is !erfectl #alid" but it was not consistent with the !rocess the described of indi#idual infections bein$ ac)uired and clearin$ inde!endentl . Biet> later described this !rocess correctl in the Garki model. /ere it is !aired with the sim!ler formulation to become the &cdonald' Biet> model.

&acdonald simulated e!idemics. In so doin$" he used e)uations similar to Ross*s first model?

13

Ross#Macdonald Style Models Se#eral models ha#e been !ublished as a Ross'&acdonald model. Aron and &a first wrote it in the followin$ wa in the ear 45H6?

This model considers infected but not infectious mos)uitoes" so it i$nores the dela for !atho$en latenc in mos)uitoes. There are se#eral wa s to consider the dela or its effects. Smith and &c8en>ie wrote down a sim!le model with two e)uations that does incor!orate mos)uito mortalit durin$ the latent !eriod but that i$nores the dela ?

@erha!s" the best sim!le im!lementation of the Ross'&acdonald model which Aron and &a formed a second model" a dela differential e)uation.

0ater" Anderson and &a wrote down the followin$ #ersion of the Ross'&acdonald model?

Integrated ontrol It is more useful to write R) in a sli$htl different" but e)ui#alent wa for the !ur!ose of describin$ control effect si>es of different inter#entions alone or in combination. It is more useful to write R) in a sli$htl different" but e)ui#alent wa . 0et denote the number of adult mos)uitoes that are born each da " di#ided b the !o!ulation densit of humans. Pnder the consensus assum!tions of the Ross'&acdonald model"
so at e)uilibrium?

An e)ui#alent e(!ression for the basic re!roducti#e number is then?

14

-ach set of terms in the models corres!onds to a different !art of the !rocess that is sub3ect to control? lar#al ecolo$ and lar#al control + ," adult blood feedin$ and sur#i#al and adult #ector control the

duration of infection and control b treatin$ infections with dru$s + =:r," usin$ #accines or dru$ chemo!ro!h la(is to block infection +b," and usin$ dru$s or #accines that block transmission from humans +c,. $he -irth of a $heory: ./001.020 %or Ross" )uantitati#e thinkin$ came naturall . &athematical models were a wa to codif " refine" and communicate the )uantitati#e lo$ic of biolo$ical !henomena" es!eciall mos)uito'borne !atho$en transmission" in a form that was ri$orous and testable. In his corres!ondence with &anson in the ear 4H5<" before successfull demonstratin$ that mos)uitoes transmit malaria" Ross was alread reasonin$ )uantitati#el about his own fe#er.Two ears later" Ross wrote about the e(termination of mos)uitoes. /e s!eculated about the mathematical laws of transmission and some of his !reliminar thou$hts about modelin$ were also a!!arent in 4596. The reasonin$ is similar to the transmission models he formulated 7 ears later" and shows he was alread thinkin$ about transmission in )uantitati#e terms. In his criti)ue of the e(!eriment at &ian'&ir" he wrote. At the time" the methods did not et e(ist to describe malaria transmission mathematicall " to measure the rele#ant constants" or to know what those constants were. Ross*s first model is" in man wa s" an e(tended criti)ue of the e(!eriment at &ian'&ir" but it did not directl address the )uestion of transmission. The model itself describes random mo#ement of adult mos)uitoes in and out of concentric >ones surroundin$ the center of an area that had been com!letel de!leted of a)uatic habitat. Ross*s anal sis of the model su$$ested that adult mos)uito densities would decline outside the ed$e of a control >one as mos)uitoes wandered into the non'control area. The !rocess would create a si$moidal $radient in mos)uito densit " and if the control >one was lar$e enou$h" an area in the middle would be mos)uito'free. Ross concluded that lar#al control could work if it could de!lete lar#al mos)uitoes in a lar$e enou$h area; but no conclusions about the #alidit of lar#al control" per se" could be reached if it had not been done intensi#el enou$h" for lon$ enou$h" at a lar$e enou$h scale. After one ear of Ross #isited &auritius to ad#ice on the control of malaria" he formulated and described a model of mos)uito'borne disease transmission in 459H in his Report on the -re!ention of %alaria in %auritius " and he e(!anded on these ideas in the first edition of his @he -re!ention of %alaria. The model was an a priori descri!tion of the number of infections in humans based on his )uantitati#e reasonin$ about the number of mos)uitoes and their infection d namics. It can be formulated as a difference e)uation as stated abo#e. At Ross*s in#itation" .aite anal >ed the model and wrote a clear descri!tion of the model assum!tions and limitations. The model was concisel !resented and anal >ed a$ain b 0otka . Ross*s main conclusions from the models were that there is a causal relationshi! between the ratio of mos)uitoes to humans and the number of infected humans and that it was not necessar to kill
15

e#er mos)uito to end transmission. The models demonstrated that there was a critical mos)uito densit " " such that $reater densities would sustain transmission while lesser ones would not. Ross*s formula +makin$ some liberal allowances in the inter!retation of !arameters, is e)ui#alent to the followin$? Ross was unsatisfied with some minor numerical discre!ancies between his results and .aite*s. These discre!ancies arose because the had !icked different time ste!s for simulation. Ross then decided to reformulate a $eneral model that would not de!end on an !articular time ste!. /e formulated the model usin$ a s stem of cou!led differential e)uations in continuous time; thou$h mathematicall different" the second model was the limitin$ case of Ross*s first model with an infinitesimall small time ste!. At the same time" he wanted to de#elo! a more e(!ansi#e theor . Ross*s second malaria transmission model was !ublished as an addendum to the second edition of @he -re!ention of %alaria in ear 4544and in Nature.

Mathematical models
Because of this !arasite*s im!ortance and com!le( life c cle models ha#e been de#elo!ed to hel! to understand its d namics. *ife cycle The !attern of alternation of se(ual and ase(ual re!roduction which ma seem confusin$ at first is a #er common !attern in !arasitic s!ecies. The e#olutionar ad#anta$es of this t !e of life c cle were reco$nised b Gre$or &endel. Pnder fa#ourable conditions ase(ual re!roduction is su!erior to se(ual as the !arent is well ada!ted to its en#ironment and its descendants share these $enes. Transferrin$ to a new host or in times of stress" se(ual re!roduction is $enerall su!erior as this !roduces a shufflin$ of $enes which on a#era$e at a !o!ulation le#el will !roduce indi#iduals better ada!ted to the new en#ironment. The ad#anta$es to ase(ual re!roduction within a host can be seen from this sim!le model taken from Cook. The !ro!ortion of hosts that are !arasitised is assumed to be small. This bein$ the case the @oisson distribution is a reasonable model. If the !arasite is self'fertili>in$ then the chance of successful re!roduction is 4 ' e'm where m is the !ro!ortion of the !o!ulation !arasitised. If the !arasite is a facultati#e bise(ual one ' one that re)uires the !resence of another !arasite on the same host the likelihood of success is 4 ' +4 M m,e'm. If the !arasite has two distinct se(es and re)uires both for re!roduction" then the chance of success is a +4 ' 6 4'n,+mn E nb e'm, where the sum is taken between n F 6 and infinit . If m F 9.4 then the chance of success of the self'fertili>in$ !arasite is U9 times that of one with distinct se(es. The chance of success of the bise(ual !arasite is twice that of the !arasite with distinct se(es. %or smaller #alues of m" the ad#anta$es of self'fertili>ation are e#en $reater. Gi#en that this !arasite s!ends !art of its life c cle in two different hosts it must use a !ro!ortion of its a#ailable resources within each host. The !ro!ortion utili>ed is currentl unknown. -m!irical estimates of this !arameter are desirable for modelin$ of its life c cle. $ransmission The basic model of transmission is known as the Ross'&acBonald model after its authors.It is a set of four cou!led non linearordinar differential e)uations. This model is also used for other mos)uito borne infections includin$ filaria and den$ue. .hile modifications to the
16

model ha#e been !ro!osed to encom!ass !articular conditions" the basic model is still re$arded as a reasonable first a!!ro(imation to most scenarios. The model is

In this model 0h is the number of susce!tible humans" 5h is the number of infected humans" 0m is the number of susce!tible mos)uitoes" 5m is the number of infected mos)uitoes" b is the bitin$ rate" A is the reco#er rate in humans" B is the mortalit rate of the mos)uitoes" @hm is the transmission rate from humans to mos)uitoes" @mh is the transmission rate from mos)uitoes to humans and N F0h M 5h. The reco#er rate is the reci!rocal of the mean of the duration of a human infection. There are a number of sim!lif in$ assum!tions in this model?

mos)uito and human !o!ulations are of constant si>e susce!tibilit of both humans and mos)uitoes to infection is constant no incubation !eriod neither humans nor mos)uitoes are or can become immune to infection both !o!ulations are well mi(ed the bitin$ rate is constant

%urthermore the e)uations are deterministic ' that is the i$nore the !ossibilit of random fluctuations. This model is not sol#able in closed form and instead re)uires numerical inte$ration. -asic reproductive number An im!ortant !arameter ' the basic re!roducti#e number + R9 , ' can be deri#ed from this model. This is the a#era$e number of new infectious hosts that a t !ical infectious human will !roduce durin$ his or her infectious !eriod. An infectious a$ent can onl !ersist if the basic re!roducti#e number is $reater than one. In the Ross'&acBonald model

17

where m is the number of mos)uitoes !er human. The term on the ri$ht of the e)uation is the !roduct of the a#era$e number of humans infected b a mos)uito and the a#era$e number of mos)uitoes infected b a human. It is worth notin$ that the bitin$ rate a!!ears here as a )uadratic term. To eliminate an infectious a$ent it is necessar to reduce the R9 to below 4. This can be achie#ed b reducin$ the bitin$ rate" reducin$ the number of mos)uitoes" shortenin$ the mos)uito life s!an or shortenin$ the duration of infection in the human. If a #accine is a#ailable it is onl necessar to #accinate 4 ' 4 E R9 !ro!ortion of the !o!ulation to eradicate the infectious a$ent as this will brin$ R9 below 4. This method of estimatin$ R9 makes a number of sim!lif in$ assum!tions

transmission rates are constant bitin$ rates are constant duration of human infection is constant mos)uito infection rates are constant

I$norin$ the #ariabilit that ma be !resent in these !arameters can lead to underestimation of R9. In the case of malaria in Africa R9 has been estimated to be I9'H4;. onclusion : This is a short note of mathematical a!!roach for e!idemic diseases. In this short note on&athematical modelin$ of infectious disease author has tried to focus on recentl stressed conce!ts. As there was no sco!e to discuss details of those de#elo!ed conce!ts or man other mathematical #iews author has confined himself with a torch li$ht #iew onl on main features. References 4. Alfredo &orabia +699U, ? A histor of e!idemiolo$ic methods and conce!ts. Birkhcuser. !. 5I. ISBN I'<7UI'7H4H'<. 6. Anderson" R. A. and R.&. &a . 4556. Infectious Biseases of /umans? B namics and Control. 2(ford Pni#ersit @ress" 2(ford P8. I. Becker" N.+45<H, ? The use of e!idemic models" Biometrics" I;. 65;1I9;. U. Baile " N. T. `. +45<;, ? The &athematical Theor of Infectious Biseases" 6nd ed. /afner. ;. Carol Buck" Al#aro 0lo!is" -nri)ue Nd3era" &ilton Terris. +455H, ? The Challen$e of -!idemiolo$ ? Issues and Selected Readin$s. Scientific @ublication No. ;9;. @an American /ealth 2r$ani>ation. .ashin$ton" BC. 6. Cla ton" Ba#id and &ichael /ills +455I, ?Statistical %odels in <pidemiolo$# 2(ford Pni#ersit @ress. ISBN 9'45'H;6664';. <. Biet>" 8. +457<, ? -!idemics and rumours? A sur#e " `. Ro . Statist. Soc. Ser. A" 4I9 ;9;1 ;6H. H. Biet>" 8. +45HH, ? The :rst e!idemic model? A historical note on @. B. -n=ko" Austral. `. Statist." I9A" ;7'7;. 5. Biet>" 8. +45HH, ? Bensit de!endence in !arasite transmission d namics" @arasit. Toda " U" 54'5<.
18

49. Biet>" 8. and Schen>le" B. +45H;, ? &athematical models for infectious disease statistics" in A Celebration of Statistics" A. C. Atkinson and S. -. %einber$" eds." S!rin$er'Aerla$" New Cork. 47<169U. 44. -llner" S.@. and `. Guckenheimer. 6997. B namic &odels in Biolo$ . @rinceton Pni#ersit @ress" @rinceton N`. 46. Gabriel Sanche> R" Sanche> Gome> 0&" Carmona 0" Ro)ue i %i$uls &" BonfillCos! K. +699;, ? /ormone re!lacement thera! for !re#entin$ cardio#ascular disease in !ost' meno!ausal women. Cochrane Batabase of S stematic Re#iews" Issue 6. Art. No.? CB996665. doi?49.4996E4U7;4H;H.CB996665.!ub6. 4I. Grassl " N. C." %raser" C. +699H, ? &athematical models of infectious disease transmissionX. Nat. Re!. %icrobiol. 3 +7,? U<<'H<. doi?49.49IHEnrmicro4HU;. @&IB 4H;II6HH. 4U. Green" &ichael B.; B. &ichal %reedman" and 0eon Gordis. +699H, ?Reference Guide on -!idemiolo$ +@B%,. %ederal `udicial Centre. 4;. /ennekens" Charles /.; `ulie -. Burin$ +45H<, ? <pidemiolo$# in %edicine. &a rent" Sherr 0. +-d.," 0i!!incott" .illiams and .ilkins. ed. ISBN 5<H'9'I47'I;7I7'<. 47. /erndn" &. A.; /erndnde>'Bfa>" S.; Robins" `. &. +699U, ? A structural a!!roach to selection bias. <pidemiolo$# 3Cambrid$e, %ass.4 .4 +;, ? 74;176;.@&IB 4;I9H576. edit. 4<. /ethcote" /... and `ames A. Corke. +45HU, ? Gonorrhea Transmission B namics and Control.+0ecture Notes in Biomathematics #ol. ;7,. S!rin$er'Aerla$" NC.A#ailable at www.math.uiowa.eduEft!EhethcoteElnb;7.!df. 4H. /ethcote" /. .. and 0e#in" S. A. /ethcote" /. .. +45H5, ? @eriodicit in e!idemiolo$ical models" in A!!lied &athematical -colo$ " 0. Gross" T. G. /allam" and S. A. 0e#in" eds." S!rin$er'Aerla$" Berlin. 45I1644. 45. /ethcote" /. .. +455U, ? A thousand and one e!idemic models" in %rontiers in Theoretical Biolo$ "S. A. 0e#in" ed." 0ecture Notes in Biomath. 499" S!rin$er'Aerla$" Berlin" 455U" !!. ;9U1;4;. 20. /istorical Be#elo!ments in -!idemiolo$ . Cha!ter 6. `ones W Bartlett 0earnin$ 00C. 64. /ill" Austin Bradford +457;, ? The -n#ironment and Bisease? Association or CausationRX. -roceedin$s of the Ro#al Societ# of %edicine 4/ +;,? 65;1 I99. @&C 4H5H;6;.@&IB 4U6HIH<5. 66. Ioannidis" `. @. A.; Tarone" R.; &c0au$hlin" `. 8. +6944, ? The %alse'!ositi#e to %alse' ne$ati#e Ratio in -!idemiolo$ic Studies. <pidemiolo$# 55 +U,? U;91 U;7.doi?49.495<E-B-.9b94IeI4H64b;97e. @&IB 64U59;9;. edit 6I. 8eelin$" &.`. and @. Rohani. 699H. &odelin$ Infectious Biseases in /umans and Animals.@rinceton Pni#ersit @ress" @rinceton N`. 6U. 8ermack" ..2. and ..G. &c8endrick. 456<. A contribution to the mathematical theor of e!idemics. @roceedin$s of the Ro al Societ of 0ondon" Series A 44;? <99'<64. 6;. 0ast" `. &. +6994, ? A dictionar of e!idemiolo$ X" Uth edn" 2(ford? 2(ford Pni#ersit @ress. ;th. edn +699H," edited b &i)uel@orta DIJ 67. &an#endra Nara an &ishra and Aina 8r. +6946, ?&athematical &odel to Simulate Infectious Bisease. VSR/C@N@D, Vol. E 324, ,79'7H. 6<. &erril" Ra &." @hB" &@/ +6949, ? An Introduction to -!idemiolo$ " %ifth -ditionT. Cha!ter 6? /istoric Be#elo!ments in -!idemiolo$ . `ones and Bartlett @ublishin$. .eb. 4< Se!t. 6946.

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6H. &i)uel@orta +699H, ? A Bictionar of -!idemiolo$ . 2(ford Pni#ersit @ress. !!. 491 44. ISBN 5<H'9'45';I4U;9'6. Retrie#ed 44 `ul 6946. 65. &orabia" Alfredo. ed. +699U, ? A /istor of -!idemiolo$ic &ethods and Conce!ts. Basel" BirkhauserAerla$. @art I. DUJ D;J I9. Neil & bur$h; Bebra `ackson +6944, ? &easurin$ /ealth and Bisease I? Introduction to -!idemiolo$ . I4. Nutter" `r." %... +4555, ? Pnderstandin$ the interrelationshi!s between botanical" human" and #eterinar e!idemiolo$ ? the Cs and Rs of it allX. <cos#s Health 4 +I,? 4I41U9. doi?49.49U7E3.4;67'9556.4555.95566.(. I6.2lsen `" Christensen 8" &urra `" -kbom A. +6949, ? An Introduction to -!idemiolo$ for /ealth @rofessionals. New Cork? S!rin$er ScienceMBusiness &edia. e'ISBN 5<H'4'UU45' 4U5<'6. II. @ai" &adhukar. +699H, ? -!idemiolo$ ? The Bi$ @ictureT. &cGill Pni#ersit ..eb. 4< Se!t. 6946. IU.@hilli!s" Carl A.; 8aren `. Goodman +699U, ? The missed lessons of Sir Austin Bradford /illX. <pidemiolo$ic -erspecti!es and Inno!ations . +I,? I. doi?49.44H7E4<U6';;<I'4' I@&C ;6UI<9. @&IB 4;;9<46H. I;.@rinci!les of -!idemiolo$ . 8e Conce!ts in @ublic /ealth. 0ondon? Sa$e P8" 6995. Credo Reference. 4 Au$. 6944. .eb. I9 Se!t. 6946. I7.Ra &. &errill +6949, ? Introduction to -!idemiolo$ . `ones W Bartlett 0earnin$.!. 6U. ISBN 9'<7I<'7766'U. I<.Rothman" 8enneth" Sander Greenland and Timoth 0ash +699H, ? &odern -!idemiolo$ " Ird -dition" 0i!!incott .illiams W .ilkins. ISBN 9'<H4<';;7U'7" ISBN 5<H'9'<H4<';;7U'4. IH.Rothman" 8enneth +6996, ? -!idemiolo$ . An introductionX" 2(ford Pni#ersit @ress. ISBN 9'45';4I;;U'<" ISBN 5<H'9'45';4I;;U'4 I5.Smetanin @." 8obak @." &o er C." &ale 2 +699;, ? The Risk &ana$ement of Tobacco Control Research @olic @ro$ramsX The .orld Conference on Tobacco 2R /ealth Conference" `ul 4614;" 6997 in .ashin$ton BC. U9.S>klo && W Nieto %` +6996,. ? -!idemiolo$ ? be ond the basics" As!en @ublishers" Inc. U4.Statistical methods in e!idemiolo$ ? 8arl @earson" Ronald Ross" &a3or Greenwood and Austin Bradford /ill" 4599 1 45U;. Trust Centre for the /istor of &edicine at PC0" 0ondon U6.Rile " S. +699<, ? 0ar$e'scale s!atial'transmission models of infectious disease.Science 6.3 +;H65,?465H 1 I94 doi?49.4467Escience.44IU75;. @&IB 4<;U9H5U. UI.Ross" R. +4547, ? An a!!lication ofthe theor of !robabilitiesto the stud of a !riori !athometr .@art I. @roceedin$s of the Ro al Societ of 0ondon" Series A 56? 69U'6I9. UU. Ronald Ross; /ilda @. /udson" +454<, ?An A!!lication of the Theor of @robabilities to the Stud of a !riori @athometr . @art IIX" @roceedin$s of the Ro al Societ of 0ondon. Series A" Aol. 5I.646'66;. htt!?EE#isualiseur.bnf.frEAisualiseurRBestinationFGallicaW2FNP&&';74H7 U;. Ronald Ross; /ilda @. /udson" +454<, ?An A!!lication of the Theor of @robabilities to the Stud of a !riori @athometr . @art III" @roceedin$s of the Ro al Societ of 0ondon. Series A" Aol. 5I.66;'6U9. htt!?EE#isualiseur.bnf.frEAisualiseurRBestinationFGallicaW2FNP&&';74H7 U<.Sattens!iel" 0. andA. 0lo d. +6995, ? The Geo$ra!hic S!read of Infectious Biseases? &odels andA!!lications. @rinceton Pni#ersit @ress" @rinceton N`.
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UH..ickwire" 8. +45<<, ? &athematical models for the control of !ests and infectious diseases? A sur#e " Theoret. @o!ulation Biol." 44.4H616IH.

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