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INTRODUCTIONTO BIOSTATISTICALAPPLICATIONS

INHEALTHRESEARCHWITH MICROSOFTOFFICEEXCEL® ANDR

INTRODUCTIONTO BIOSTATISTICAL APPLICATIONSIN HEALTHRESEARCH WITHMICROSOFT OFFICEEXCEL® ANDR

SecondEdition

ROBERTP.HIRSCH

FoundationfortheAdvancedEducationintheSciences Bethesda,MD,USA

Thissecondeditionfirstpublished2021 ©2021JohnWiley&Sons,Inc.

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PARTONEBASICCONCEPTS1

1THINKINGABOUTCHANCE3

1.1PropertiesofProbability / 4

1.2CombinationsofEvent / 8

1.2.1Intersections / 8

1.2.2Unions / 13

1.3Bayes’Theorem / 16

ChapterSummary / 19

Exercises / 20

2DESCRIBINGDISTRIBUTIONS25

2.1TypesofData / 26

2.2DescribingDistributionsGraphically / 27

2.2.1GraphingDiscreteData / 27

2.2.2GraphingContinuousData / 30

2.3DescribingDistributionsMathematically / 36

2.3.1ParameterofLocation / 37

2.3.2ParameterofDispersion / 41

2.4TakingChanceintoAccount / 48

2.4.1StandardNormalDistribution / 49

ChapterSummary / 59

Exercises / 62

3EXAMININGSAMPLES65

3.1NatureofSamples / 66

3.2Estimation / 67

3.2.1PointEstimates / 67

3.2.2TheSamplingDistribution / 73

3.2.3IntervalEstimates / 78

3.3HypothesisTesting / 82

3.3.1RelationshipBetweenIntervalEstimationand HypothesisTesting / 89

ChapterSummary / 91

Exercises / 93

4UNIVARIABLEANALYSISOFACONTINUOUS DEPENDENTVARIABLE101

4.1Student’s t-Distribution / 103

4.2IntervalEstimation / 106

4.3HypothesisTesting / 109

ChapterSummary / 113

Exercises / 114

5UNIVARIABLEANALYSISOFANORDINALDEPENDENT VARIABLE119

5.1NonparametricMethods / 120

5.2Estimation / 123

5.3WilcoxonSigned-RankTest / 124

5.4StatisticalPowerofNonparametricTests / 128

ChapterSummary / 128

Exercises / 129

6UNIVARIABLEANALYSISOFANOMINALDEPENDENT VARIABLE133

6.1DistributionofNominalData / 134

6.2PointEstimates / 135

6.2.1Probabilities / 136

6.2.2Rates / 138

6.3SamplingDistributions / 142

6.3.1BinomialDistribution / 143

6.3.2PoissonDistribution / 146

6.4IntervalEstimation / 149

6.5HypothesisTesting / 151

ChapterSummary / 155

Exercises / 156

PARTTHREEBIVARIABLEANALYSES161

7BIVARIABLEANALYSISOFACONTINUOUSDEPENDENT VARIABLE163

7.1ContinuousIndependentVariable / 163

7.1.1RegressionAnalysis / 165

7.1.2CorrelationAnalysis / 189

7.2OrdinalIndependentVariable / 207

7.3NominalIndependentVariable / 207

7.3.1EstimatingtheDifferencebetweentheGroups / 208

7.3.2TakingChanceintoAccount / 209

ChapterSummary / 218

Exercises / 221

8BIVARIABLEANALYSISOFANORDINALDEPENDENT VARIABLE227

8.1OrdinalIndependentVariable / 228

8.2NominalIndependentVariable / 236

ChapterSummary / 241

Exercises / 243

9BIVARIABLEANALYSISOFANOMINALDEPENDENT VARIABLE245

9.1ContinuousIndependentVariable / 246

9.1.1Estimation / 247

9.1.2HypothesisTesting / 255

9.2NominalIndependentVariable / 258

9.2.1DependentVariableNotAffectedbyTime:Unpaired Design / 259

9.2.2HypothesisTesting / 266

9.2.3DependentVariableNotAffectedbyTime:Paired Design / 277

9.2.4DependentVariableAffectedbyTime / 283

ChapterSummary / 286

Exercises / 288

10.1ContinuousIndependentVariables / 296

10.1.1MultipleRegressionAnalysis / 297

10.1.2MultipleCorrelationAnalysis / 317

10.2NominalIndependentVariables / 319

10.2.1AnalysisofVariance / 320

10.2.2PosteriorTesting / 331

10.3BothContinuousandNominalIndependentVariables / 340

10.3.1Indicator(Dummy)Variables / 341

10.3.2InteractionVariables / 343

10.3.3GeneralLinearModel / 348

ChapterSummary / 355 Exercises / 358

11.1NonparametricAnova / 369

11.2PosteriorTesting / 375

ChapterSummary / 380

Exercises / 381

12MULTIVARIABLEANALYSISOFANOMINALDEPENDENT

12.1Continuousand/orNominalIndependentVariables / 387

12.1.1MaximumLikelihoodEstimation / 387

12.1.2LogisticRegressionAnalysis / 389

12.1.3CoxRegressionAnalysis / 399

12.2NominalIndependentVariables / 401

12.2.1StratifiedAnalysis / 402

12.2.2RelationshipBetweenStratifiedAnalysisandLogistic Regression / 410

12.2.3LifeTableAnalysis / 414

ChapterSummary / 424

Exercises / 427

13TESTINGASSUMPTIONS433

13.1ContinuousDependentVariables / 436

13.1.1AssumingAGaussianDistribution / 437

13.1.2TransformingDependentVariables / 477

13.1.3AssumingEqualVariances / 485

13.1.4AssumingAdditiveRelationships / 494

13.1.5DealingWithOutliers / 506

13.2NominalDependentVariables / 507

13.2.1AssumingaGaussianDistribution / 507

13.2.2AssumingEqualVariances / 510

13.2.3AssumingAdditiveRelationships / 511

13.3IndependentVariables / 511

ChapterSummary / 513

Exercises / 516

PREFACETOFIRSTEDITION

Regardlessofwhetheryouareahealthresearcherorsomeonewhowantsto understandthehealthresearchliterature, IntroductiontoBiostatisticalApplications inHealthResearchwithExcel willprovideyouwithabasicunderstandingofthe mostcommonlyusedstatisticalmethodsinhealthresearch.Thefocusofthistextis onlearningstatisticalconceptsandinterpretingtheresultsofperformingstatistical tests.Thetextisintendedforreaderswhoarenotnecessarilymathematically minded.Toaccomplishthis,Iprovideplainlanguageexplanationsandgraphic representationsofstatisticalconceptsratherthanrelyingonpurelymathematical descriptionsthataretypicalofmanystatisticaltexts.Thus,thereadersof IntroductiontoBiostatisticalApplicationsinHealthResearchwithExcel cancometo understandandappreciatestatisticallogicwithaminimumlevelofmathematical ability.

Thistextincludesmanyexamplesthatarepatternedafteractualanalysesof healthresearchdata.Theseexamplesusetwoapproachestoillustratestatistical principles.Someexamples,namelythosethatillustratesimplerstatisticalmethods, areworkedout“byhand”toallowabetterunderstandingofthestatisticalmethod. Manyoftheexamples,however,involvestatisticalmethodsthatwouldrequiremore complicatedcalculationsthataretypicallyperformedbyastatisticalprogram.My experienceisthatlittleornounderstandingofthelogicbehindthesemethodsis gainedbyperformingthesecalculationsbyhand.Instead,wewillbelearninghow touseExcel® toperformtheseanalysesandunderstandtheresults.

Ibelievethathealthresearchersandstudentsofhealthresearchwillfind IntroductiontoBiostatisticalApplicationsinHealthResearchwithExcel tobehighly accessibleduetoitsinterpretationratherthancalculation-orientedpresentation. xiii

Also,theoverallformatofthetextisdesignedsothatappropriatestatisticalmethods foraparticularsetofdatacanbeeasilylocated.Thetextisdividedintofourparts. Thefirstofthesebuildsthefoundationofstatisticallogic.Theremainingchapters increaseincomplexitybybuildingonsimplermethods.Thesepartsaddressunivariable,bivariable,andmultivariableanalysisrespectively.Withineachpart,there arethreechapters.Theseaddressmethodsforcontinuous,ordinal,andnominal dependentvariables.Thesechaptersareorientedtoreflectauniqueflowchartthat isprovidedinanappendixandinthetext.Thisflowchartservesasastatistical roadmapsothatifthereaderisabletoidentifythetypeofdatarepresentedby thedependentvariableandindependentvariable(s)theywillbeabletoselectthe correctstatisticalmethodtoanalyzetheirdata.Atthebeginningofeachchapter, acontinuationoftheflowchartreinforcesthemethodsdiscussedinthatchapter andhowthestatisticalmethodsareselected.Ibelievethattheoveralldesignof thistextallowseventhemostmathematicallychallengedreaderstoreallyunderstandstatisticalmethodsusedinhealthresearchbyprovidingahighlyverbaland visualexplanationofstatisticsinalogicalprogressionthatbuildsonitselfwhile alsoprovidingthenecessarytoolsinaneasilyretrievableform.

MyprincipalreasonforwritingatextusingExcelistoprovidethereaderwith accesstodataanalysiswithouthavingtodependonastatisticalprogrammer.My reasoningwasthatExcelisacommonlyavailableprogramthatincludestools neededtoperformmoststatisticalanalyses.1 Inadditiontowhatisalreadypart ofExcel,IamprovidingBAHR(Biostatistical Applicationsin Health Research) programsforExcelthatgivethereadertheabilitytoperformallofstatistical analyses,aswellasthedatasetsusedintheexamples.Thesecanbefoundat www .website.com.

IamgoingtoassumethatthereaderhasabasicknowledgeofExcel.Ifyouhave neverusedExcel(orotherspreadsheetprogram),youcanreadtheExcelPrimerin AppendixD.EvenifthisisyourfirsttimeusingExcel,Ithinkyouwilllearnvery quicklyasmuchasyouwillneedtoperformthestatisticaltestsdescribedinthis textbook.

OnethingyouneedtodobeforeyoustartusingExcelforstatisticalanalyses istoinstalltwoadd-ins.TheseareprogramsthatcomewithExcel,buttheyare inactiveunlesstheuseractivatesthem.Todothis,clickon“FILE”onthemain menubar.Thenclickon“Options”followedby“Add-ins.”Onthenextscreen,you willsee“Manage”:followedbyaselectionbox.Select“ExcelAdd-ins”andclick on“Go … ”Thiswilldisplayamenuthatliststheavailableadd-ins.Makesurethat thereisacheckintheboxesfor“SolverAdd-inand“AnalysisToolpak”2 Now,you willseeanewclassinthe“DATA”selectionfromthemainmenu.Thatclassis called“Analysis.”3 Wewillbeusingitsoon.

1 ThisistrueformostMacusersaswellasPCusers.

2 ForMacusers,theonlyadd-inavailableis“SolverAdd-in.”Youcanperformthesameprocedures(and alotmore)bydownloadingthefreeversionofStatPlus,whichcanbefoundontheinternet.

3 ForStatPlus,thecommandsappearinthetopmenubar.

PREFACETOSECONDEDITION

Thereareaseveralchangesinthesecondedition.Themostobviousistheadditionofathirteenthchapter.Thischapterdiscussestheassumptionsthatunderlie thestatisticalmethodsdescribedinChapters4–12.Inthischapter,youwilllearn howtoidentifytheassumptionsforaparticularstatisticaltestandhowtoevaluate whethertheassumptionsaresatisfied.Further,youwilllearnwhatcanbedoneif theassumptionisnotsatisfied.

Tofurtheraidinidentifyingassumptions,AppendixChasbeenchanged.In thisappendix,alloftheflowchartsarepresented.Theversionsoftheflowcharts inAppendixChaveaddedindicatorsoftheassumptionsmadebyeachtest.

AnotherchangeinthesecondeditionistheinclusionofexamplesinusingRto performthestatisticalanalysesdescribedinChapters4–12.Risafreecollectionof statisticalprograms,whichisgaininginpopularityinintroductorystatisticstexts. Forthemostpart,RisanalternativetoExcelforanalysis,butExcelremainssuperiorfordatamanagement.DatasetsgeneratedinExcelcanbeimportedintoRfor analysisthere.AppendixEgivesaprimerforR.There,youwilllearnhowtoaccess RandgetitrunningonyourcomputeraswellassomeofthebasicusesofR.

ProvidedwiththistextbookonthecompanionwebsiteisanewversionofBAHR programsforExcel.Inthisnewversionarenewprogramsfornonparametricanalyses,Student–Newman–Keulstests,andstratifiedanalyses.Withthesenewprograms,itislessnecessarytoperformcalculationsbyhandand,instead,letthe computerperformthemforus.Themethodsforperfumingtestsbyhandarestill includedinthetextforthosewhofindthathelpsthemunderstandthestatistical logic.

Attheendofeachchapterachaptersummaryandexercisesfromthefirstedition oftheworkbookhavebeenadded.Theanswerstotheoddexercisesappearin AppendixF.

Maryland,2020

ABOUTTHECOMPANIONWEBSITE

Thisbookisaccompaniedbyastudentcompanionwebsiteandaninstructorcompanionwebsite: www.wiley.com/go/hirsch/healthresearch2e

Thestudentcompanionwebsiteincludes

• Workbook

• Datasets

• Exceladd-in

• Instructionsforinstallingtheadd-in

TheinstructorcompanionwebsiteincludestheSolutionsManual.

PARTONE BASICCONCEPTS

Statisticiansareusedtodealingwithuncertainty.Evenso,thereisonefactofwhich evenstatisticiansarecertain:thefactthatwe,ashealthresearchersandpractitioners,arealwaysinterestedinapplyingtheresultsofastudytopersons,places,and/or timesthatwerenotincludedinthestudy.Ourpurposeistointerpretastudy’sobservationsastheyrelatetosomelargergroup.Instatisticalterms,thelargergroupis calledthe population andthesmallergroupiscalledthe sample.Asweinterpret healthresearchdatafromaparticularsample,itisalwayswiththeintentionofusing thesample’sobservationstodrawsomeconclusionaboutthepopulationfromwhich thatsamplewastaken.

Sincewearealwaysinthepositionofusingasampletounderstandthepopulation,itisimportantthatwetakesamplessothateachoneisrepresentativeofthe population.Unfortunately,wedonotknowhowtodothat.Toappreciatetheproblem,letusthinkaboutapopulationthatweunderstandcompletely.Forinstance, supposeweweretothinkaboutadeckof52cards.Inthis“population”thereare twocharacteristicsofitsmembers:suitandrank.Thesecharacteristicsaredistributeduniformlyamongthemembersofthepopulationsothatthereare13cards ineachof4suitsandeachsuithas13ranksfromdeucetoace.Now,thinkingof thatwell-definedpopulation,whichfivecardswouldyouusetocommunicatethe structureofthepopulation?

IntroductiontoBiostatisticalApplicationsinHealthResearchwithMicrosoftOfficeExcel® andR, SecondEdition.RobertP.Hirsch. ©2021JohnWiley&Sons,Inc.Published2021byJohnWiley&Sons,Inc. Companionwebsite: www.wiley.com/go/hirsch/healthresearch2e

Ifyoufeelfrustratedwiththisquestion,itisbecausethereisnocompletelycorrectanswer.Anysetoffivecardsfailstocommunicatepreciselythestructureof thedeck.

Ifweareunabletoselectarepresentativesamplefromsuchawell-definedpopulation,imagineselectingarepresentativesamplefromapopulationthatisreally ofinteresttohealthresearchers.Itjustcannotbedone!

Eventhoughwedonotknowhowtomakeeachsamplerepresentativeofthe population,wedoknowhowtomakeacollectionofsamplesrepresentativeofthe population.Wecandothatwiththedeckof52cardsbyshufflingthedeckand dealingseveral“samples”of5cards.Inotherwords,wecouldletchancedetermine whichmembersofthepopulationaregoingtobeincludedineachsample.Any particularhandoffivecardsmightbedistinctlyunrepresentativeofthedeck,butif wecontinuedtodealhandsoffivecards,inthelongrunthosehandswouldrepresent thedeck.Wedothesamethingwhenwetakesamplesfrompopulationsaspartof research.Weletchancedeterminewhichmembersofthepopulationendupinthe sample.

Itisthisprincipleof randomsampling thatmakesitnecessarytounderstandthe roleofchancewhenweareinterestedininterpretingtheresultsofhealthresearch. Theprimarypurposeofstatisticsistoconsiderhowchanceinfluencesthatinterpretation.Tobeinterpretersofhealthresearchdata,weneedtorecognizethatthe samplesweexaminemight,justbychance,besubstantiallydifferentfromtherest ofthepopulation.Todothis,weneedtobecomfortableininterpretingtheresults ofstatisticalanalyses.Itisthepurposeofthistexttohelpyoudevelopthatlevelof comfort.

Tounderstandstatistics,weneedtounderstandhowchanceinfluencesobservationsinasampleandhowtheroleofchancecanbetakenintoaccount.Thus,we beginthistextbyexaminingthecharacteristicsofchanceandhowwecanusethe sample’sobservationstodrawconclusionsaboutthepopulation.First,inChapter 1,wewilllookatchanceitselftounderstandhowitworks.Next,inChapter2, wewillexaminethecharacteristicsofapopulationtodiscoverhowitsdatacanbe described.Finally,inChapter3,wewillconcentrateonthesampletoseehowthe sample’sobservationscanbeusedtodescribethepopulation.Onceweunderstand thesebasicprinciples,wewillbereadytotakealookatstatisticalproceduresthat arecommonlyusedinhealthresearch.

CHAPTER1

THINKINGABOUTCHANCE

1.1PropertiesofProbability4

1.2CombinationsofEvent8

1.2.1Intersections8 1.2.2Unions13

1.3Bayes’Theorem16 ChapterSummary19 Exercises20

Intheintroductiontothisfirstpartofthetext,welearnedthatchanceisusedtoselect samplesfromthepopulationthatare,inthelongrun,representativeofthepopulationfromwhichtheycame(Figure1.1).Beforewecanappreciatehowchance influencesthecompositionofthosesamples,however,weneedtounderstandsome thingsaboutchanceitself.Inthischapter,wewilllookatthebasicpropertiesof chanceandseehowthechancesofindividualeventscanbecombinedtoaddress healthissues.

IntroductiontoBiostatisticalApplicationsinHealthResearchwithMicrosoftOfficeExcel® andR, SecondEdition.RobertP.Hirsch. ©2021JohnWiley&Sons,Inc.Published2021byJohnWiley&Sons,Inc. Companionwebsite: www.wiley.com/go/hirsch/healthresearch2e

Figure1.1 Chancedetermineswhichdatavaluesinthepopulationendupinthesample.

1.1PROPERTIESOFPROBABILITY

Tobeginwith,weshouldpointoutthattherearetwotermsthatcanbeusedinterchangeably: chance and probability.Ineverydaylanguage,probability(orchance) tellsushowmanytimessomethinghappensrelativetothenumberoftimesitcould happen.Forexample,wemightthinkoftheprobabilitythatapatientpresenting withasorethroathasstreptococcalpharyngitis.Ifwecanexpect1patienttoactuallyhavestreptococcalpharyngitisoutofevery10patientsseenwithasorethroat, thentheprobabilityofhavingstreptococcalpharyngitisis0.10.Orequivalently, thereisa10%chancethatapersonselectedatrandomfromamongpersonswith sorethroatswouldhavestrepthroat.

Instatisticalterminology,thenumberoftimessomethinghappensiscalledits frequency andthat“something”iscalledan event.Theopportunitiesforaneventto occurarecalled observations. 1 Whenusingtheconceptofprobability,weneedto understandthattherearetwopossibleresultsforeachobservation:eithertheevent occursortheeventdoesnotoccur.Inthepreviousexample,theeventwasstreptococcalpharyngitisandthepatientsseenwithasorethroatweretheobservations.

Everydaylanguageisoftencumbersomewhendiscussingissuesinstatistics. Analternativeapproachistoexamineeventsandobservationsgraphically.Wedo thisbyconstructinga Venndiagram.InaVenndiagram,weusearectangleto symbolizealloftheobservationsandacircletosymbolizethoseobservationsin whichtheeventoccurs.Figure1.2isaVenndiagramwecouldusetothinkabout theprobabilitythatapatientwithasorethroathasstreptococcalpharyngitis.

TherearesomeaspectsofobservationsandeventsthatareevidentinaVenn diagram.Forinstance,wecanseethattheentirerectangleoutsideofthecirclecorrespondstoobservationsinwhichtheeventdoesnotoccur.Whenaneventdoesnot occur,wesaythatthe complement oftheeventoccurs.Inthiscase,theeventis havingstrepthroatanditscomplementisnothavingstrepthroat.

ThewayaVenndiagramtellsusaboutthemagnitudeoftheprobabilityisbythe areaofthecirclerepresentingtheeventrelativetotheareaoftheentirerectangle.A waywecancomparetheseareasisbycreatinga Vennequation.AVennequation

1 Statisticiansalsorefertotheopportunityforaneventtooccurasa trial.Sincetheterm trial refers toaclinicalexperimentinhealthresearch,wewillexclusivelyusetheterm observation torefertothe opportunityforaneventtooccur.

Figure1.2 AnexampleofaVenndiagram.Therectangulararearepresentsallobservations. Thecirculararearepresentstheobservationsinwhichtheeventoccurs.Theareawithinthe rectanglebutoutsideofthecirclerepresentsthoseobservationsinwhichtheeventdidnot occur.

Figure1.3 AVennequationillustratingtheprobabilityapatientwithsorethroathasstreptococcalpharyngitis.

usesthepartsofaVenndiagraminamathematicalequationthatshowshowthe probabilityofaneventiscalculated.Fortheprobabilitythatapatientwithsore throathasstreptococcalpharyngitis,theVennequationwouldlooklikeFigure1.3. AVennequationhelpsusseeanotherpropertyofprobabilitiesthatprobabilitieshaveadistinctrangeofpossiblevalues.Sinceaneventcannotexistwithoutan observation,thecirclecanonlybeasbigastherectangle.Inotherwords,thenumeratormustbeasubsetofthedenominator.Theresultofthispropertyistomakethe largestpossiblevalueforaprobabilityequalto1(or100%).Thevalueof1occurs wheneveryobservationinthedenominatorisalsoaneventinthenumerator.When

Probability of strep throat =
All patients with sore throat
Patients with strep throat

theprobabilityofanobservationbeinganeventhasavalueof1,itis certain that theeventwilloccur.

Thenumeratorofaprobabilitycontainsthenumberofevents.Thelargestvalue possibleisequaltothenumberofobservations.Thesmallestvaluepossibleis0.If thenumeratorofaprobabilityisequalto0,thisimpliesthatnoneoftheobservations areeventsand,therefore,theprobabilityisequalto0aswell.Aprobabilityof0 indicatesthatitis impossible foraneventtooccur.Aprobabilitycanbenosmaller than0andnolargerthan1.2

Whenwewanttocalculateaprobability,itiseasiertousesomemathematicalshorthand.Tosymbolizeaprobability,weusealowercase p followedbyaset ofparentheses.Withinthoseparentheses,weidentifytheeventaddressedbythe probability.Then,theequationlookslikethis:

p(event)= numberofevents numberofobservations (1.1)

Next,letustakealookatanexamplethatillustratescalculationofaprobability anditsinterpretation.

◼ EXAMPLE1.1

Supposewedidthroatculturesfor100patientswhocomplainedofasorethroat and10ofthosecultureswerepositiveforstreptococcus.Whatistheprobabilitya personpickedatrandomwouldhaveapositivestrepculture?

Inthisquestion,apositivestreptestistheeventandsomeonewithsorethroat isanobservation.Tocalculatetheprobabilityofapersonhavingapositivestrep culture,wecanuseEquation(1.1).

p(event)= numberofevents numberofobservations = 10

Thus,thereisaprobabilityof0.1(ora10%chance)thatapersonselectedfromthe groupofpatientswithasorethroatwouldbepositiveforstreptococcus. ◼

Apartoftheshorthandweusetoshowhowprobabilitiesarecalculatedconcerns thecomplementofanevent(i.e.,anobservationinwhichtheeventdoesnotoccur). Ratherthaninsertingthedescriptionofthecomplementoftheeventwithinthe parentheses,wemoreoftenputabaroverthedescriptionoftheevent.So,p(event) standsfortheprobabilityofthecomplementoftheeventoccurring(i.e.,theprobabilityoftheevent not occurring).Forthecomplementofhavingstrepthroat,we coulduse p(strep).Therearetwopropertiesofacollectionofeventsthatanevent anditscomplementalwaysdemonstrate.Thefirstis mutualexclusion.Acollection ofeventsissaidtobemutuallyexclusiveifitisimpossiblefortwoormoreevents

2 Thisrangeofpossiblevaluesbetween0and1meansthataprobabilityisalsoaproportion.

tooccurinasingleobservation.Inthiscase,itiscertainlyimpossibleforaperson bothtohavestrepthroatandtonothavestrepthroat.

Thesecondpropertyofaneventanditscomplementisthattheyare collectively exhaustive.Acollectionofeventsissaidtobecollectivelyexhaustiveifevery observationiscertaintoconsistofatleastoneoftheevents.Here,thisimplies thateverypersonwithasorethroateitherhasordoesnothavestrepthroat.Clearly, thisistrue.

Foreventsthatarebothmutuallyexclusiveandcollectivelyexhaustive(likean eventanditscomplement),thereisaspecialrelationshipamongtheevents:the sumoftheirprobabilitiesisequalto1.Inmathematicallanguage,therelationship betweentheprobabilityofaneventoccurringandtheprobabilityofthecomplement oftheeventoccurringisshowninEquation(1.2):

Alittlebitofalgebrashowsusthatwecancalculatetheprobabilityofthecomplementofaneventbysubtractingtheprobabilityoftheeventfrom1.Thisisshown inEquation(1.3):

ThisrelationshipcanalsobedescribedingraphiclanguageasintheVennequation inFigure1.4.

Sofar,wehaveseenhowwecanthinkaboutprobabilitiesusingeverydaylanguage,graphiclanguage,andmathematicallanguage.Eachoneofthesewaysof examiningstatisticalissueshasitsownadvantages.Thesortofthingswehave

Figure1.4 AVennequationillustratingtherelationshipbetweentheprobabilityofthe complementoftheevent(e.g.,nothavingstrepthroat)andtheprobabilityoftheevent(e.g., havingstrepthroat).

learnedaboutprobabilityincludesthefactthatprobabilitieshaveadiscreterangeof possiblevaluesrangingfrom0(indicatingthattheeventcannotoccur)to1(indicatingthattheeventalwaysoccurs).Also,wehaveexaminedtherelationshipbetween aneventanditscomplement.Thisrelationshiphastwoimportantpropertiesof acollectionofevents.Thesepropertiesaremutuallyexclusiveandcollectively exhaustive.Acollectionofeventsismutuallyexclusiveifonlyoneoftheevents canoccurinasingleobservation.Tobecollectivelyexhaustive,thecollectionof eventsneedstoencompasseverypossibilitysothatatleastoneoftheeventsoccurs ineveryobservation.Next,wewilltakealookatotherkindsofcollectionsofevents.

1.2COMBINATIONSOFEVENT

Therearetwowayswemightbeinterestedinhowtwoormoreeventsrelatetoeach other.Onewayisthattheeventsoccurtogetherinthesameobservation.Wecall thisthe intersection ofevents.Anotherwayisthatatleastoneeventoccursinan observation.Wecallthisthe union ofevents.

1.2.1Intersections

Inhealthresearchandpractice,weareofteninterestedinsituationsinwhichmore thanoneeventoccursinasingleobservation.Forinstance,wemightbeinterested intherelationshipbetweenahigh-fatdietanddevelopmentofatherosclerosis.The sortsofpeopleinwhomwewouldbemostinterestedarethosewhohavebothof thoseevents,sincetheyaretheonesforwhomahigh-fatdietcouldhavecontributed totheriskofdisease.

Instatisticalterminology,werefertotheoccurrenceoftwoormoreevents inasingleobservationastheintersectionoftheevents.Figure1.5illustratesthe

Figure1.5 Venndiagramillustratingtherelationshipbetweenahigh-fatdietanddevelopmentofatherosclerosis.Theareainwhichthecirclesoverlaprepresentsthosepersonswho havebothahigh-fatdietandatherosclerosis.

probabilitiesofahigh-fatdietandatherosclerosisandtheintersectionofthose twoevents.Theirintersectioniswherethetwocirclesoverlap.Thesearethe observationsinwhichapersonhasbothahigh-fatdietandatherosclerosis.

Theprobabilityofanobservationincludingbothevents(i.e.,theintersection ofthoseevents)considersthesizeoftheoverlaprelativetoalltheobservations. Figure1.6showsaVennequationrepresentingtheprobabilityoftheintersectionof high-fatdietandatherosclerosis.

Ifwewanttocalculatetheprobabilityofanintersectionofevents,weusewhat iscalledthe multiplicationrule.Toseehowthemultiplicationruleworks,letus beginwithaVennequation(Figure1.7).

TotheleftoftheequalssignintheVennequationinFigure1.7istheprobability oftheintersectionofhavingahigh-fatdietanddevelopingatherosclerosisasshown inFigure1.6.Inthenumeratorofthatprobabilityarethepersonswhohadboth events.Inthedenominatorareallpersonsregardlessofdietordisease.Immediately totherightoftheequalssignistheprobabilitythatsomeonehasahigh-fatdiet.In thenumeratorofthatprobabilityarethepersonswithahigh-fatdietandinthe denominatorare,asbefore,allpersonsregardlessofdietordisease.

p (fat and atherosclerosis) =

persons

Figure1.6 Vennequationfortheprobabilitythatapersonhasbothahigh-fatdiet(fat)and hasatherosclerosis.Inthenumeratoristheareaofoverlap(intersection)ofthetwocircles intheVenndiagram(Figure1.5).Thedenominatorrepresentseveryonewhetherornotthey haveahigh-fatdietoratherosclerosis(i.e.,theentirerectangle).

persons

persons

Figure1.7 Vennequationofthemultiplicationruleusedtocalculatetheintersectionof high-fatdietandatherosclerosis.

Thesecondfractiontotherightoftheequalssignalsoisaprobability,3 butit looksdifferentfromanyprobabilitywehaveencounteredsofar.Specifically,itdoes notincludealltheobservations(representedbytherectangleinaVenndiagram)in itsdenominator.Rather,itincludesonlythosepersonswithahigh-fatdietinits denominator.Thisisanexampleofaveryimportantkindofprobability,calleda conditionalprobability. Aconditionalprobabilitytellsustheprobabilityofan eventoccurringgiventhatanothereventhasoccurred.Inthiscase,theconditional probabilitytellsustheprobabilityofapersonhavingatherosclerosisgiventhatthe personhasahigh-fatdiet.

Inmathematicalnotation,aconditionalprobabilityalsolooksdifferentfrom otherprobabilitieswehaveencountered.Equation(1.4)illustratesthemathematical notationfortheVennequationinFigure1.7.

where

p(A and B) = probabilitythatanobservationwillincludebothevent A andevent B (i.e.,theprobabilityoftheintersectionof A and B)4

p(A) = probabilitythatanobservationincludesevent A (i.e.,theunconditional probabilityofevent A)

p(B ∣ A) = probabilitythatanobservationwillincludeevent B giventhatit includesevent A (i.e.,aconditionalprobabilityofevent B)

Or,intermsofahigh-fatdietandatherosclerosis,

Fromastatisticalpointofview,itdoesnotmatterwhicheventisaddressedbythe conditionalprobability.5 Thus,theprobabilityoftheintersectionofhigh-fatdiet andatherosclerosiscouldalsobecalculatedas

3 Recallthat,tobeaprobability,afraction’snumeratormustbeasubsetofitsdenominator.Thisisthe casehere,becausethosepersonswithbothahigh-cholesteroldietandatherosclerosis(thenumerator) areallincludedinthecirclerepresentingpersonswithatherosclerosis(thedenominator).

4 Insetnotation,thisis p(A ∩ B).

5 Thewaytheprobabilityoftheintersectioniscalculateddependsonlyonwhichprobabilitiesare obtainedaspartofaparticularhealthresearchstudy.Ifourinformationabouttherelationshipbetween thehigh-fatdietandatherosclerosiscomesfromacohortstudy(astudyinwhichtheprobabilityofdiseaseiscomparedbetweenexposedandunexposedpersons),forexample,theconditionalprobabilitywe wouldmeasureistheprobabilityofthediseasegivenexposurestatus.Inacase–controlstudy(astudyin whichtheoddsofbeingexposediscomparedbetweenpersonswhohaveanddonothavethedisease), however,theconditionalprobabilitywemeasureistheprobabilityoftheexposuregiventhedisease status.

InEquations(1.5)and(1.6),wecanseethataverticallineisusedtoseparatethe twoeventsintheparenthesesofaconditionalprobability.Theeventtotheleftofthe verticallineiscalledthe conditionalevent.Itistheconditionaleventthattheprobabilityaddresses.InEquation(1.5),theconditionaleventishavingatherosclerosis,so thisconditionalprobabilitytellsusaboutthechancethatsomeonehasatherosclerosis.Theeventtotherightoftheverticallineiscalledthe conditioningevent. Theconditioningeventdefinesthecircumstanceinwhichweareinterestedinthe probabilityoftheconditionalevent.Here,havingahigh-fatdietistheconditioning event.Thus,Equation(1.5)tellsusthatweareinterestedintheprobabilityofhaving atherosclerosisgiven(i.e.,underthecondition)thatsomeonehasahigh-fatdiet. Thereasonthatconditionalprobabilitiesaresoimportantinhealthresearchis thefactthattheytellusaboutanimportantaspectoftherelationshipbetween events.Namely,conditionalprobabilitiescanbeusedtoseeiftheoccurrenceofone eventchangestheprobabilityoftheoccurrenceofanotherevent.If,forexample, weareinterestedinwhetherthereisthissortofrelationshipbetweenahigh-fat dietandhavingatherosclerosis,wecouldcomparetheconditionalprobabilityin Equation(1.5)withtheprobabilitythatsomeonehasatherosclerosisgiventhatthey donothaveahigh-fatdiet(p(atherosclerosis ∣ fat)).Ifthosetwoconditionalprobabilitieshavethesamevalue,thenwecanconcludethatahigh-fatdietdoesnot influencethechanceofhavingatherosclerosis.Inthatcase,thethreeprobabilities inEquation(1.7)areallequaltothesamevalue.

Or,inmoregeneralterms,

p(B ∣ A)= probabilitythatanobservationwillincludeevent B giventhatitdoes notincludeevent A (i.e.,anotherconditionalprobabilityofevent B)

Instatisticalterminology,wesaytwoeventsare statisticallyindependent when theprobabilityofoneoftheeventsisnotaffectedbyoccurrenceoftheotherevent.6 Inbiologicterms,eventsthatarestatisticallyindependentcannothaveacausalrelationship(oranyothertypeofrelationship).

6 Theterm“statisticallyindependent”asstatisticiansuseitcanbeconfusingwhenweconsidertheeverydaymeaningof“independence.”Ifweweretosay,forexample,thattwopersonsareindependent,we arelikelytoinferthatthereisnoconnectionbetweenthem.Thisisnotwhatthestatisticianisimplying.Rather,thestatisticianissayingthatyoudonotneedtoconsiderwhetherornotoneeventhas occurredwhenaddressingtheprobabilityofanotherevent.Whenastatisticianimpliesthatthereisno overlapbetweenevents,thestatisticiansaysthattheyare“mutuallyexclusive”ratherthan“statistically independent.”

Todetermineifeventsarestatisticallyindependent,weneedtocompareonlytwo ofthethreeprobabilitiesinEquation(1.8).Ifthosetwoprobabilitiesareequaltothe samevalue,thenallthreeprobabilitiesarethesameandtheconditionalandconditioningeventsarestatisticallyindependent.Wewilltakealookatanexampleofthis relationshipshortly,butfirstletusseehowconditionalprobabilitiesarecalculated.

Tocalculateaconditionalprobability,weuseEquation(1.4)algebraicallyrearrangedasinEquation(1.9).

Or,intermsofahigh-fatdietandhavingatherosclerosis,

ThisprocessofidentifyingstatisticalindependenceisillustratedinExample1.2.

◼ EXAMPLE1.2

Supposethat,inaparticularvalleyoftheMojaveDesert,thereare2,500residents. Ofthose2,500residents,625workforACMEBorax,Inc.,acompanythatrecovers chemicalsfromthebrineunderasaltflatthatcoversmostofthevalleyfloor.Ofthe 2,500residentsofthevalley,500havebeendiagnosedwithleukemia.Ofthe500 diagnosedwithleukemia,125arepersonswhoworkforACMEBorax,Inc.Given thatinformation,isworkingforACMEstatisticallyindependentofbeingdiagnosed withleukemia?

First,letusconsidertherelationshipbetweenworkingforACMEandhaving leukemia.Wearetoldthat625personsworkforACMEand,ofthose,125have leukemia.Fromthatinformation,wecancalculatetheprobabilityofhaving leukemiaundertheconditionthatapersonworksforACMEusingEquation(1.9): p(leukemia ∣ ACME)= p(leukemiaandACME) p(ACME) = 125∕2,500 625∕2,500 = 0.2

TodetermineifworkingforACMEandhavingleukemiaarestatisticallyindependentevents,weneedtocomparethatconditionalprobabilitywitheithertheprobabilityofhavingleukemiagiventhatapersondoesnotworkforACMEorwiththe overall(i.e.,unconditional)probabilityofhavingleukemia.Thelatterprobabilityis

p(leukemia)= numberwithleukemiainvalley numberinvalley = 500 2,500 = 0.2

Sincethesetwoprobabilitiesareequaltothesamevalue,wecanconcludethatworkingforACMEandhavingleukemiaarestatisticallyindependentevents.Inother words,workingforACMEdoesnotchangetheprobabilityofhavingleukemia. ◼

Sofar,wehaveseenthatwecanusethemultiplicationruletocalculatetheprobabilityoftwoeventsoccurringinasingleobservation(i.e.,theintersectionofthose events).Tocalculatetheprobabilityoftheintersectionofmorethantwoevents, wesimplyincludeeachadditionaleventinthemultiplicationofconditionalprobabilities.Foreachadditionalevent,weincludetheconditionalprobabilityofthe eventwiththeconditioningeventsbeingalloftheeventslistedpreviouslyinthe equation.Forexample,wecancalculatetheintersectionofthreeeventsasshown inEquation(1.11).

where

p(C ∣ A and B) = probabilitythatanobservationwillincludeevent C givenit includesevents A and B (i.e.,aconditionalprobabilityofevent C)

Iftheeventsarestatisticallyindependent,wecanuseasimplifiedversionofthe multiplicationrule.Thissimplificationistomultiplytheunconditionalprobabilities oftheevents.Equation(1.12)showsthesimplifiedversionfortheintersectionof threeeventsexaminedinEquation(1.11).

Thereasonwecanusethissimplifiedversionofthemultiplicationruleisthat,by definition,theconditionalandunconditionalprobabilitiesarethesameforstatisticallyindependentevents(asshowninEquation(1.8)).Ifthethreeeventsarenot statisticallyindependent,however,weneedtouseEquation(1.11)tocalculatethe intersectionofevents.

1.2.2Unions

Whenourinterestisintheprobabilityofany(i.e.,1ormore)ofacollectionofevents occurringinthesameobservation,wesayweareinterestedintheunionofthose events.Suppose,forexample,weareconsideringtworiskfactorsforatherosclerosis:high-fatdietandsmoking.Inthatcase,wemightbeinterestedincalculatingthe probabilityapersonhasatleastoneoftheseriskfactors(i.e.,eitherhigh-fatdietor smokingorbothhigh-fatdietandsmoking).Toillustratethis,letusaddsmoking totheVenndiagraminFigure1.5.ThentheVenndiagramofallthreeeventswill looksomethingliketheoneinFigure1.8.

Theunionofthetworiskfactorsissatisfiedifapersoneitherhasahigh-fatdiet orsmokes(orboth).Thus,thenumeratoroftheprobabilityoftheunionofthose twoeventsincludesthepartoftheVenndiagramcoveredbyeithercircle.

Atherosclerosis

Figure1.8 Venndiagramshowingtherelationshipbetweenhigh-fatdiet,smoking,and atherosclerosis.

p (fat and/or smoke) =

All persons

Figure1.9 Vennequationshowingtheprobabilityoftheunionofsmokingand/orhigh-fat diet

Figure1.9showstheVennequationfortheunionofsmokingandhigh-fatdiet. Tocalculatetheprobabilityoftheunionoftwoevents,weusethe additionrule. Asthenameimplies,intheadditionruletheprobabilitiesofeachoftheeventsare addedtogether.

Sinceaddingtheprobabilitiestogetherincludestheintersectionofthoseevents twice,theprobabilityoftheintersectionoftheeventsmustbesubtractedfromthe sum.Thiscalculationfortheunionofsmokingandahigh-fatdietisillustratedby theVennequationinFigure1.10.

persons

personsAll personsAll persons

Figure1.10 Vennequationshowingcalculationoftheunionofsmokingandahigh-fatdiet usingtheadditionrule.

Inmathematicalterms,thecalculationoftheunionoftwoeventsisperformed asshowninEquation(1.13).

where

p(A and/or B) = probabilityanobservationwillincludeevent A and/orevent B (i.e.,theprobabilityoftheunionofevents A and B)7

Now,letustakealookatanexampleaddressingtheunionoftwoevents.

◼ EXAMPLE1.3

Supposeweareplanningaclinicaltrialofanewlivevaccine.Inthisstudy,wewant toexcludepersonswhoareeitherpregnantorimmunocompromised.Supposewe estimatethatthepopulationfromwhichweareplanningtotakeoursampleincludes 20%ofthetotalnumberofpersonswhoarepregnantand10%ofthetotalnumberof personswhoareimmunocompromised.Ifbeingpregnantandbeingimmunocompromisedarestatisticallyindependentevents,whatproportionofoursamplewill beexcludedduetoeitherofthesecharacteristics?

Tocalculatetheprobabilityoftheunionoftwoevents,weuseEquation(1.13). Forthisapplication,Equation(1.13)lookslikethefollowing: p(pregand∕orcomp)= p(preg)+ p(comp)− p(pregandcomp)

Weknowtheprobabilitythatapersonselectedatrandomfromthepopulationwill bepregnant(p(preg) = 0.2)andtheprobabilitythatapersonselectedatrandomfrom

7 Insetnotation,thisis p(A ∪ B).

thepopulationwillbeimmunocompromised(p(comp) = 0.1).Wearenotgiventhe probabilityoftheintersectionofthesetwoevents(i.e.,theprobabilityaperson willbebothpregnantandimmunocompromised).Wearetold,however,thatthese twoeventsarestatisticallyindependent.Thistellsusthatwecanusethesimplified versionofthemultiplicationruleillustratedforthreestatisticallyindependentevents inEquation(1.12).Forthetwostatisticallyindependenteventsofbeingpregnant andbeingimmunocompromised,theirintersectioncanbecalculatedasfollows:

Nowthatwehavetheprobabilityoftheintersectionofthetwoevents,weareready tocalculatetheirunion.

Thus,wecanexpectthat28%ofthepersonsweselectfromthepopulationwillbe excludedfromthestudybecausetheyareeitherpregnantorimmunocompromised (orboth).

Aswiththemultiplicationruleweusedtocalculatetheprobabilityoftheintersectionofevents,theadditionruleforcalculationoftheprobabilityoftheunion ofeventshasasimplifiedversionthatcanbeusedunderaspecialcondition.For theadditionrule,theconditionisthattheeventsaremutuallyexclusive.Ifso,the probabilityoftheunionofeventscanbecalculatedbysimplyaddingtogetherthe probabilitiesoftheevents.Theintersectionsoftheeventsdonotneedtobesubtractedfromthatsumbecause,bydefinition,theprobabilityoftheintersectionof twomutuallyexclusiveeventsisequalto0.

1.3BAYES’THEOREM

Earlier,welearnedtherearetwotypesofeventsinaconditionalprobability:the conditionalevent(s)andtheconditioningevent(s).Wealsolearnedthatthesetypes ofeventshaveverydifferentrolesinaconditionalprobability.Theconditionalevent istheeventforwhichtheprobabilityiscalculated(i.e.,conditionalprobabilitiestell usthechanceoftheconditionaleventoccurring).Allofthecharacteristicsofunconditionalprobabilities(thosediscussedatthebeginningofthischapter)applytothe conditionalevent.Forinstance,theprobabilityofthecomplementoftheconditional eventisfoundbysubtractingtheconditionalprobabilityfrom1(seeEquation(1.3)). Equation(1.14)showsthatrelationshipforconditionalprobabilities:

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