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HowtoCriticallyAppraiseanArticle
JaneMYoung,MichaelJSolomon NatClinPractGastroenterolHepatol.20096(2):8291.

SummaryandIntroduction
Summary

Criticalappraisalisasystematicprocessusedtoidentifythestrengthsandweaknessesofaresearcharticlein ordertoassesstheusefulnessandvalidityofresearchfindings.Themostimportantcomponentsofacritical appraisalareanevaluationoftheappropriatenessofthestudydesignfortheresearchquestionandacareful assessmentofthekeymethodologicalfeaturesofthisdesign.Otherfactorsthatalsoshouldbeconsidered includethesuitabilityofthestatisticalmethodsusedandtheirsubsequentinterpretation,potentialconflictsof interestandtherelevanceoftheresearchtoone'sownpractice.ThisReviewpresentsa10stepguidetocritical appraisalthataimstoassistclinicianstoidentifythemostrelevanthighqualitystudiesavailabletoguidetheir clinicalpractice.


Introduction

Topracticeevidencebasedmedicine,cliniciansneedtoapplythefindingsofscientificresearchtothe circumstancesofindividualpatientsaspartoftheirclinicaldecisionmakingprocess.Clinicians,therefore,must beabletoselectandappraisescientificliteraturethatisrelevanttotheirfield,understandtheimplicationsof researchfindingsforindividualpatients,elicitpatients'ownpreferencesanddevelopanappropriatemanagement planbasedonthecombinationofthisinformation.Eachofthesetaskspresentsitsownchallenges,butthe sheervolumeofmedicalliteraturemeansthatthefirststep(thatofselectingandappraisingscientificevidence) canbedaunting.Thenumberofnewmedicalresearcharticlespublishedeachyearcontinuallyincreases,and morethan12,000newarticles,includingpapersoninexcessof300randomizedcontrolledtrials(RCTs),are addedtotheMEDLINEdatabaseeachweek.[1,2]Onepracticalwaythatclinicianscanmanagethis'information overload'[2]istodevelopefficientskillsincriticalappraisal,whichenablethemfocusononlythehighestquality studiesthatwillguidetheirclinicalpracticeandtoextrapolateinformationwhennecessaryfromstudiesofless rigorousdesignifhighqualitytrialsareunavailable. Criticalappraisalhasbeendefinedasthe"...applicationofrulesofevidencetoastudytoassessthevalidityof thedata,completenessofreporting,methodsandprocedures,conclusions,compliancewithethicalstandards, etc.Therulesofevidencevarywithcircumstances."[3]Althoughthemethodologicalcriteriabywhichthevalidity ofastudyisassessedwillvaryaccordingtoitsdesign,somegeneralprinciplesunderpintheevaluationofany researchstudy.Variousguidelinesandassessmenttoolshavebeendevelopedtoprovideastructuredapproach totheprocessofcriticalappraisalforclinicians.[414] Despitetheplethoraofdocumentsavailabletoguidetheprocess,no'goldstandard'instrumentforcritical appraisalexists.Thecriteriausedtoassessthevalidityandrelevanceofscientificliteraturearenotstaticthey mustevolvewithimprovementsinunderstandingoftheimportantsourcesofbiasinherentindifferentstudy designs,andincreasedawarenessofthepotentialinfluenceofothernonmethodologicalfactors,suchasconflicts ofinterest.[15]Astructuredapproachtocriticalappraisalcouldpotentiallyimprovethequalityofthisprocess,and simplechecklistscanbeusefultoscreenoutresearchthatisoflowqualityoroflittlerelevance.[16]ThisReview presentsaguidetothecriticalappraisalprocess.

SelectionandCriticalAppraisalofResearchLiterature
Tenkeyquestions()canbeusedtoassessthevalidityandrelevanceofaresearcharticle.Thesequestionscan assistclinicianstoidentifythemostrelevant,highqualitystudiesthatareavailabletoguidetheirclinical

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practice.
Box1.TenQuestionstoAskwhenCriticallyAppraisingaResearchArticle

Isthestudyquestionrelevant? Doesthestudyaddanythingnew? Whattypeofresearchquestionisbeingasked? Wasthestudydesignappropriatefortheresearchquestion? Didthestudymethodsaddressthemostimportantpotentialsourcesofbias? Wasthestudyperformedaccordingtotheoriginalprotocol? Doesthestudytestastatedhypothesis? Werethestatisticalanalysesperformedcorrectly? Dothedatajustifytheconclusions? Arethereanyconflictsofinterest?
IstheStudy'sResearchQuestionRelevant?

Evenifastudyisofthehighestmethodologicalrigor,itisoflittlevalueunlessitaddressesanimportanttopic andaddstowhatisalreadyknownaboutthatsubject.[17]Theassessmentofwhethertheresearchquestionis relevantisinevitablybasedonsubjectiveopinion,aswhatmightbecrucialtosomewillbeirrelevanttoothers. Nonetheless,thefirstquestiontoaskofanyresearcharticleiswhetheritstopicisrelevanttoone'sownfieldof work.


DoestheStudyAddAnythingNew?

Scientificresearchendeavorisoftenlikenedto'standingontheshouldersofgiants',becausenewideasand knowledgearedevelopedonthebasisofpreviouswork.[18]Seminalresearchpapersthatmakeasubstantive newcontributiontoknowledgearearelativerarity,butresearchthatmakesanincrementaladvancecanalsobe ofvalue.Forexample,astudymightincreaseconfidenceinthevalidityofpreviousresearchbyreplicatingits findings,ormightenhancetheabilitytogeneralizeastudybyextendingtheoriginalresearchfindingstoanew populationofpatientsorclinicalcontext.[17]


WhatTypeofResearchQuestionDoestheStudyPose?

Themostfundamentaltaskofcriticalappraisalistoidentifythespecificresearchquestionthatanarticle addresses,asthisprocesswilldeterminetheoptimalstudydesignandhaveamajorbearingontheimportance andrelevanceofthefindings.Awelldevelopedresearchquestionusuallyidentifiesthreecomponents:thegroup orpopulationofpatients,thestudiedparameter(e.g.atherapyorclinicalintervention)andtheoutcomesof interest.[10]Ingeneral,clinicalresearchquestionsfallintotwodistinctcategories,below. QuestionsAbouttheEffectivenessofTreatment.Thesetypesofquestionsrelatetowhetheronetreatmentis betterthananotherintermsofclinicaleffectiveness(benefitandharm)orcosteffectiveness. QuestionsAbouttheFrequencyofEvents.Suchquestionsrefertotheincidenceorprevalenceofdiseaseor otherclinicalphenomena,riskfactors,diagnosis,prognosisorpredictionofspecificclinicaloutcomesand

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investigationsonthequalityofhealthcare.
WastheStudyDesignAppropriatefortheResearchQuestion?

Studiesthatanswerquestionsabouteffectivenesshaveawellestablishedhierarchyofstudydesignsbasedon thedegreetowhichthedesignprotectsagainstbias.MetaanalysesofwellconductedRCTsandindividualRCTs providethemostrobustevidencefollowedbynonrandomizedcontrolledtrials,cohortstudies,casecontrol studies,andotherobservationalstudydesigns.[19,20]However,insomecircumstances,RCTsareeithernot feasibleorconsideredethicallyinappropriate.Theseissuesaremorecommoninnonpharmaceuticaltrials,such asthoseofsurgicalprocedures.Onereviewofgastrointestinalsurgicalresearchfoundthatonly40%ofresearch questionscouldhavebeenansweredbyanRCT,evenwhenfundingwasnotanimpediment.Patients' preferences,therarityofsomeconditions,andtheabsenceofequipoiseamongsurgeonsprovedtobethemajor obstaclestoperformingRCTsofgastrointestinalsurgeryinthissetting.[21]WhenanRCTisnotfeasible,the specificreasonsthatprecludeitsusewilldeterminethetypeofalternatestudydesignthatcanbeused.[21] Observationalstudies,ratherthanRCTs,arethemostappropriatestudydesignforresearchquestionsonthe frequencyofevents.
DidtheStudyMethodsAddresstheKeyPotentialSourcesofBias?

Inepidemiologicalterms,thepresenceofbiasdoesnotimplyapreconceptiononthepartoftheresearcher,but rathermeansthattheresultsofastudyhavedeviatedfromthetruth.[3]Biascanbeattributedtochance(e.g.a randomerror)ortothestudymethods(systematicbias).Randomerrordoesnotinfluencetheresultsinany particulardirection,butitwillaffecttheprecisionofthestudy[22]bycontrast,systematicbiashasadirection andresultsintheoverestimationorunderestimationofthe'truth'.Systematicbiasesarisefromthewayinwhich thestudyisconducted,beithowstudyparticipantswereselected,howdatawascollected,orthroughthe researchers'analysisorinterpretation.[23] Differentstudydesignsarepronetovaryingsourcesofsystematicbias.Oncethestudydesignofagivenarticle hasbeenidentified,werecommendthatcliniciansuseoneoftheavailabledesignspecificcriticalappraisal checkliststodecidewhetherthestudyinquestionisofhighquality.TheCriticalAppraisalSkillsProgramme (CASP)includessuchtoolsandtheprogramcoordinatorshavedevelopedseparatechecklistsfortheappraisalof systematicreviews,RCTs,cohortstudies,casecontrolstudies,diagnosticteststudies,economicevaluations andqualitativeresearchthateachcomprise10questions.[9]TheyhavebeendevelopedfromtheUsers'guidesto themedicalliteratureseriesofarticlesthatwereoriginallypublishedintheJournaloftheAmericanMedical Association.Thesearticlesarenowavailableinbookform[5]andarereadilyaccessibleontheinternet.[9]
SystematicReviewsandMetaanalyses

Ameticulous,standardizedprotocolisusedinasystematicreviewtoidentify,criticallyappraiseandsynthesize alltherelevantstudiesonaparticulartopic.Somesystematicreviewsmaythenproceedtoametaanalysis,in whichtheresultsfromindividualstudiesarecombinedstatisticallytoproduceasinglepooledresult.[3]Although planningtoundertakeasystematicrevieworametaanalysisprospectivelyispossible,[24]themajorityofthese typesofarticleareretrospectiveandariskofbiasexists,whicharisesfromtheselectionofstudiesandthe qualityoftheseprimarysources.[25]Publicationbias,whichresultsfromtheselectivepublicationofstudieswith positivefindings,isofparticularconcern,asitdistortsoverallperceptionsofthefindingsonaparticulartopic.


[26,27]

TheQUORUM(QualityofReportingofMetaAnalyses)statementprovidesacomprehensiveframeworkfor assessmentsofthequalityofreportinginmetaanalysesandsystematicreviews.[25,28]Inaddition,the AMSTAR[29]assessmenttool,whichcomprises11questions,hasbeendevelopedfortheappraisalof systematicreviews,andthistoolortheCASPchecklist[9]couldbemoreusefulthantheQUORUMstatementfor clinicianswhowishtoundertakearapidappraisalofthesetypesofarticles.Keymethodologicalpointsto considerintheappraisalofsystematicreviewsandmetaanalysesarelistedin.


Box2.KeyMethodologicalPointstoConsiderintheAppraisalofSystematicReviewsandMetaanalyses

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Wereallrelevantstudiesincluded(i.e.wasthesearchcomprehensive,diditexcludearticlesonthebasisof publicationstatusorlanguageandwasthepotentialforpublicationbiasassessed)? Wereselectedarticlesappraisedanddataextractedbytwoindependentreviewers? Wassufficientdetailprovidedabouttheprimarystudies,includingdescriptionsofthepatients,interventions andoutcomes? Wasthequalityoftheprimarystudiesassessed? Didtheresearchersassesstheappropriatenessofcombiningresultstocalculateasummarymeasure? SystematicreviewsandmetaanalysesarenotrestrictedtoRCTsalone.TheMOOSE(MetaAnalysisOf ObservationalStudiesinEpidemiology)guidelineshavebeendevelopedasacorollaryoftheQUORUM statementformetaanalysesofnonRCTs.[30]
RandomizedControlledTrials

InanRCT,therandomallocationofparticipantsshouldensurethattreatmentgroupsareequivalentintermsof bothknownandunknownconfoundingfactorsanydifferencesinoutcomesbetweengroupscan,therefore,be ascribedtotheeffectoftreatment.[31]Studydesignalone,however,willnotguardagainstbiasifcrucialaspects ofthestudyprotocolaresuboptimal.Thepotentialforselectiveenrollmentofpatientsintothestudycanbeone animportantsourceofbiasifthegrouptowhichindividualswillbeallocatedisknownorcanbeguessed.[32] Centralizedmethodsofrandomization,forexampleacomputergeneratedallocation,arepreferabletoless concealedmethods,suchasuseofcolorcodedformsorpseudorandomsequencesbasedonmedicalrecord numbersordaysoftheweek.[31]Failuretoconcealtheallocationsequencehasbeenshowntoresultinagreater distortionoftheresultsthanlackofdoubleblindinganothermajorsourceofbiasinRCTs.[33] TheCONSORT(ConsolidatedStandardsofReportingTrials)statementflowchart(Figure1)isfunctionally equivalenttotheQUORUMstatementforsystematicreviews,andprovidesacomprehensivetoolwithwhichto assessthestandardofreportinginrandomizedtrials.[34]KeypointstoconsiderintheappraisalofanRCTare listedin.
Box3.KeyMethodologicalPointstoConsiderintheAppraisalofRandomizedControlledTrials

Wastheprocessoftreatmentallocationtrulyrandom? Wouldparticipantshavebeenabletoknoworguesstheirtreatmentallocation? Wereparticipantsandresearchers'blinded'toparticipants'treatmentgroup? Wereoutcomesassessedobjectively? Wereallparticipantswhowererandomlyallocatedatreatmentaccountedforinthefinalanalysis? Wereallparticipants'dataanalyzedinthegrouptowhichtheywererandomlyallocated?a


aSeesectiononintentiontotreatanalysisunder'Werethestatisticalanalysesperformedcorrectly?'

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Figure1. Consolidatedstandardsofreportingtrials(CONSORT)statementflowchartforthestandardreportingand appraisalofrandomizedcontrolledtrials.WithpermissionfromCONSORT


CohortStudies

Cohort,orlongitudinal,studiesinvolvefollowinguptwoormoregroupsofpatientstoobservewhodevelopsthe outcomeofinterest.Prospectivecohortstudieshavebeenlikenedtonaturalexperiments,asoutcomesare measuredinlargegroupsofindividualsoverextendedperiodsoftimeintherealworld.[35]Cohortstudiescan alsobeperformedretrospectivelysuchstudiesusuallyinvolveidentifyingagroupofpatientsandfollowingup theirprogressbyexaminingrecordsthathavebeencollectedroutinelyorforanotherpurpose,suchasmedical data,deathregistryrecordsandhospitaladmissiondatabases. Themajormethodologicalconcernwithcohortstudiesistheirhighpotentialforselectionbiasandconfounding factors.Theseproblemsareparticularlyrelevantwhencohortstudies(ornonRCTs)areusedtoevaluate therapeuticinterventions.Inthissituation,thetreatmentthatsomeonereceivesisdeterminedbythepatient'sor clinician'spreferences,referralpatterns,currenttreatmentparadigmsorlocalpolicy.[36]Importantdifferencesare likelytoexistbetweenpatientswhoreceivedisparatetreatmentsandthesedifferences,ratherthanthetreatment itself,mightberesponsiblefortheobservedoutcomes.Althoughsomepotentialconfoundingfactorscanbe measuredandaccountedforintheanalysis,[37]suchadjustmentsaremoredifficultinretrospectivethan prospectivestudies,asdataonimportantpotentialconfoundersmightnothavebeencollected,ormightbeof

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poorquality. TheSTROBE(StrengtheningtheReportingofObservationalStudiesinEpidemiology)statementisthecorollary oftheQUORUMandCONSORTstatementsforobservationalstudies,includingcohort,casecontrolandcross sectionalstudies.[38]Keymethodologicalfeaturestoconsiderintheappraisalofcohortstudiesarelistedin.


Box4.KeyMethodologicalPointstoConsiderintheAppraisalofaCohortStudy

Isthestudyprospectiveorretrospective? Isthecohortrepresentativeofadefinedgrouporpopulation? Wereallimportantconfoundingfactorsidentified? Wereallimportantexposuresand/ortreatments,potentialconfoundingfactorsandoutcomesmeasured accuratelyandobjectivelyinallmembersofthecohort? Werethereimportantlossestofollowup? Wereparticipantsfollowedupforasufficientlengthoftime?


CasecontrolStudies

Casecontrolstudiesarealwaysretrospectivebytheirverynaturethecasepatientsareselectedbecausethey havealreadydevelopedtheoutcomeofinterest(e.g.adisease).Dataarethencollectedaboutfactorsthatmight haveinfluencedthisoutcome,andtheseexposuresarecomparedwiththoseofagroupofpeoplewhodifferfrom thecasepatientsonlyinthattheyhavenotdevelopedtheoutcomeofinterest.Casecontrolstudiesareidealfor theinvestigationofriskfactorswhentheoutcomeofinterestisrare,asitwouldtaketoolongtorecruita prospectivecohort. Majormethodologicaldifficultieswithcasecontrolstudiesaretheselectionofappropriatecontrolindividualsand thepossibilityof'recallbias'(apatient'ssubjectiveinterpretationofwhatcausedtheirconditioncanaltertheir recallofcertaineventsorexperiences).Controlsshouldbedrawnfromexactlythesamepopulationasthe cases,andtheonlydifferencebetweencontrolsandcasesshouldbethatthecontrolshavenotdevelopedthe conditionofinterest.Althoughobjectivemeasuresofpossiblecausativefactorsarepreferable,casecontrol studiesoftenrelyonparticipants'recall,andpatientsmightbemorelikelytoremembercertaineventsor experiencesthancontrols.[39]Keyaspectstoconsiderwhenassessingacasecontrolstudyarelistedin.
Box5.KeyMethodologicalPointstoConsiderintheAppraisalofaCaseControlStudy

Werethecasesclearlydefined? Werethecasesrepresentativeofadefinedpopulation? Howwerethecontrolsselectedandweretheydrawnfromthesamepopulationasthecases? Werestudymeasuresidenticalforcasesandcontrols? Werestudymeasuresobjectiveorsubjectiveandisrecallbiaslikelyiftheyweresubjective?


CrosssectionalAnalyses

Crosssectionalstudiesprovidea'snapshot'inwhichallparameters(exposuresandoutcomes)areassessedat

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thesametimeexamplesofcrosssectionaldesignsincludeoneoffsurveysandauditsofpractice.Key methodologicalpointstoconsiderintheappraisalofacrosssectionalstudyarelistedin.
Box6.KeyMethodologicalPointstoConsiderintheAppraisalofaCrosssectionalStudy

Wasthestudysampleclearlydefined? Wasarepresentativesampleachieved(e.g.wastheresponseratesufficientlyhigh)? Wereallrelevantexposures,potentialconfoundingfactorsandoutcomesmeasuredaccurately? Werepatientswithawiderangeofseverityofdiseaseassessed?


CaseSeries

Caseseriesprovidelowlevelevidenceabouttherapeuticeffectivenesshowever,thesearticlesarevery commoninmedicalliterature.Keymethodologicalissuestoconsiderwhenassessingsucharticlesarelistedin.
Box7.KeyMethodologicalPointstoConsiderintheAppraisalofaCaseStudy

Werecasesidentifiedprospectivelyorretrospectively? Arethecasesarepresentativesample(e.g.aconsecutiveseriesofindividualsrecruitedfrommultiplecenters) andsimilartopatientsinyourpractice? Wereallrelevantexposures,potentialconfoundingfactorsandoutcomesmeasuredaccurately?


StudiesthatAssesstheAccuracyofDiagnosticTests

Thesestudiesareusuallycrosssectionalindesign,butpossessanumberofspecificmethodologicalissuesthat shouldbeconsideredinadditiontothosenotedabove.[40]Toinvestigatetheaccuracyofadiagnostictest,itis performedonasampleofpatientsandtheresultsarecomparedwiththoseofareferenceorgoldstandard diagnostictest.[41]Thelevelofagreementbetweentheinvestigatedtestandthegoldstandarddiagnostictest canthenbereportedeitherintermsofthesensitivityandspecificity,orlikelihoodratio.[4,41] TheSTARD(StandardsfortheReportingofDiagnosticAccuracyStudies)websiteprovidesadetailedflowchart (Figure2)and25itemchecklistforstandardizedreportingandappraisalofstudiesthatassesstheaccuracyof diagnostictests.[42,43]TheCASPalsoprovidesasimilar,butmoresimple,toolforthistypeofstudy.[9] Importantfeaturestoconsiderwhenappraisingastudyofdiagnosticaccuracyarelistedin.


Box8.KeyMethodologicalPointstoConsiderintheAppraisalofaStudyofDiagnosticAccuracy

Doesthesampleofpatientsrepresentthefullspectrumofpatientswithandwithoutthediagnosisofinterest? Wasthereacomparisonwithanappropriate'goldstandard'test? Didallpatientsreceiveboththetestunderevaluationandthesame'goldstandard'test? Werethetestsperformedindependentlywithblindingofassessorstotheresultsofthe'goldstandard'test? Werethecutoffsthatwereusedtoclassifypatientsashavingapositivetestresultclearlydescribed?

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Figure2. Standardsforthereportingofdiagnosticaccuracystudies(STARD)statementflowchartforthestandard reportingandappraisalofstudiesexaminingtheaccuracyofdiagnostictests.WithpermissionfromSTARD


EconomicEvaluations

Economicevaluationstudiesfocusoncostefficiency,orwhichtreatmentcanprovidethegreatestbenefitforthe leastcost.[44]Severaltypesofeconomicevaluationstudiesexist,includingcostbenefit,costeffectivenessand costutilityanalyses,allofwhichdifferinhowtheymeasurehealthbenefits.[45]Animportantfeatureofcritical appraisalofanycostanalysisisanassessmentofhowwellthevariouscostsandconsequencesofindividual treatmentshavebeenidentifiedandmeasured.TheCASPhasdevelopedachecklisttoaidwiththeappraisalof economicevaluationstudies.[9]


WastheStudyPerformedinLinewiththeOriginalProtocol?

Deviationsfromtheplannedprotocolcanaffectthevalidityorrelevanceofastudy.Oneofthemostcommon problemsencounteredinclinicalresearchisthefailuretorecruittheplannednumberofparticipants.Anestimate suggeststhatmorethanathirdofRCTsrecruitlessthan75%oftheirplannedsample.[46]Thisdeviationfrom thestudyplannotonlypotentiallyreducestheextenttowhichtheresultsofthestudycanbegeneralizedtoreal worldsituations,becausethosewhoactuallywererecruitedmightbedifferentfromthosewhoweren'tforsome reason,butalsoreducesthepowerofthestudytodemonstratesignificantfindings.Otherdifferencestothe originalprotocolmightincludechangestotheinclusionandexclusioncriteria,variationintheprovidedtreatments orinterventions,changestotheemployedtechniquesortechnologies,andchangestothedurationoffollowup.

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DoestheStudyTestaStatedHypothesis?

Ahypothesisisaclearstatementofwhattheinvestigatorsexpectthestudytofindandiscentraltoany researchasitstatestheresearchquestioninaformthatcanbetestedandrefuted.[3]Anullhypothesisstates thatthefindingsofastudyarenodifferenttothosethatwouldhavebeenexpectedtooccurbychance. Statisticalhypothesistestinginvolvescalculatingtheprobabilityofachievingtheobservedresultsifthenull hypothesisweretrue.Ifthisprobabilityislow(conventionallylessthan1:20orP<0.05),thenullhypothesisis rejectedandthefindingsaresaidtobe'statisticallysignificant'atthatacceptedlevel. Studyhypothesesmustcruciallybeidentifiedapriori(thatis,beforethestudyisconducted,andaredeveloped fromtheoryorpreviousexperience).Ifthestudyinvestigatesthestatisticalsignificanceofassociationsthatwere notprespecifiedintheoriginalhypothesis(posthocanalysis),suchanalysesarepronetofalsepositivefindings because,atasignificancelevelof5%(P=0.05),1in20associationstestedwillbesignificant(positive)by chancealone.Whenalargenumberofsuchtestsareconductedsomefalsepositiveresultsarehighlylikelyto occur.Anotherimportantconsiderationittocheckthatalldatarelevanttothestatedstudyobjectiveshavebeen reported,andthatselectedoutcomeshavenotbeenomitted. Wheretreatmentsforamedicalconditionalreadyexist,trialscanbedesignedtotestwhetheranewtherapyhas similarefficacytoanexistingone.Thistypeoftrialiscalledanequivalenceornoninferioritytrial,asitspurpose istoestablishthatthenewtreatmentisnoworsethantheexistingone.[47]Equivalencestudiesrequirethatthe degreeofoutcomedifferenceatwhichthetwotreatmentswillnotbeconsideredequivalentbedeterminedin advance.[48]Forexample,researchersmightdecidethatiftheprimaryoutcomeforanewtreatmentisnogreater than5%worsethanthatoftheexistingtreatment,thetwotreatmentswillbeconsideredtobeequivalent. Equivalencestudiesdeterminewhetheranewtreatmentisatleastasgoodasanexistingtreatmentsothat decisionsaboutwhichtreatmenttoadministertoagivenpatientcanbemadeonthebasisofcriteria,suchas costoreaseofadministration.[47,48] TheCONSORTstatementforrandomizedtrialshasbeenextendedtoincorporateguidelinesforreporting equivalencestudies.[49]Akeyquestionwhenappraisingthistypeofstudyiswhetherthetrialresultswere analyzedappropriatelyforanequivalencestudy.Ifastudyisdesignedtoshowthatanewtreatmentisatleast asgoodasanexistingtreatment,statisticalmethods,forconventionaltestingofahypothesisthatonetreatment issuperiortoanothershouldnotbeused.Appropriateanalysisoftheresultsinanequivalencestudyoften involvescalculatingconfidenceintervalsforthetreatmenteffect,anddeterminingwhethertheselimitsarewithin thepredeterminedmarginofnoninferiority.[48]Anotherkeyquestioniswhetherthesamplesizewascalculated correctlyforanequivalencestudy,asthesetypesofstudyusuallyrequirealargersamplesizethana correspondingsuperioritytrial.[49]
WeretheStatisticalAnalysesPerformedCorrectly?

Assessingtheappropriatenessofstatisticalanalysescanbedifficultfornonstatisticians.However,all quantitativeresearcharticlesshouldincludeasegmentwithintheir'Method'sectionthatexplainsthetoolsused inthestatisticalanalysisandtherationaleforthisapproach,whichshouldbewrittenintermsthatareappropriate forthejournal'sreadership.Inparticular,theapproachtodealingwithmissingdataandthestatisticaltechniques thathavebeenappliedshouldbespecifiedpatientswhoarelostinfollowupandmissingdatashouldbeclearly identifiedinthe'Results'section.Originaldatashouldbepresentedinsuchawaythatreaderscancheckthe statisticalaccuracyofthepaper. AnimportantconsiderationinthestatisticalanalysisofRCTsiswhetherintentiontotreat(ITT)orperprotocol analyseswereconducted.AccordingtotheITTprinciple,participants'dataareanalyzedwithreferencetothe grouptowhichtheywererandomlyallocated,regardlessofwhethertheyactuallyreceivedtheallocated treatment.ITTanalysesarepreferred,becausetheymaintaintherandomizationandensurethatthetwo treatmentgroupsarecomparableatbaseline.[50]However,ifalotofparticipantsarenonadherantoralarge proportioncrossovertoothertreatments,anITTanalysiswillbesomewhatconservativeandtheresultsmight bedifficulttointerpret.Inthissituation,aperprotocolanalysisthatincludesonlythosepatientswhocomplied

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withthetrialprotocolcanbeusedtosupplementtheITTanalysis.Asperprotocolanalysesareatincreasedrisk ofselectionbias,theyshouldnotusuallybeusedastheprimarymethodofanalysisunlessacompellingreason existstojustifythisapproach.[50]TheCONSORTflowchart(Figure1)enablestheflowofparticipantsandthe groupsusedintheanalysisofthetrialtobeclearlyidentified.[34]


DotheDataJustifytheConclusions?

Thenextconsiderationiswhethertheconclusionsthattheauthorspresentarereasonableonthebasisofthe accumulateddata.Sometimesanoveremphasisisplacedonstatisticallysignificantfindingsthatinvoke differencesthataretoosmalltobeofclinicalvaluealternatively,someresearchersmightdismisslargeand potentiallyimportantdifferencesbetweengroupsthatarenotstatisticallysignificant,oftenbecausesamplesizes weresmall.Otherissuestobewaryofarewhethertheauthorsgeneralizedtheirfindingstobroadergroupsof patientsorcontextsthanwasreasonablegiventheirstudysample,andwhetherstatisticallysignificant associationshavebeenmisinterpretedtoimplyacauseandeffect.


AreThereanyConflictsofInterest?

Conflictsofinterestoccurwhenpersonalfactorshavethepotentialtoinfluenceprofessionalrolesor responsibilities.[51]Membersofaresearchteammustmakejudgmentsthathavethepotentialtoaffectthe safetyoftheparticipantsandthevalidityoftheresearchfindings.Researchersareinapositiontodecidewhich studieswillbeconductedintheirunit,whichpatientswillbeinvitedtoparticipateinastudyandwhethercertain clinicaloccurrencesshouldbereportedasadverseevents.[52]Thesedecisionsrequireresearcherstoactwith integrityandnotforpersonalorinstitutionalgain. Potentialfinancialconflictsofinterestincludethereceiptofsalaryandconsultationfeesfromthecompanythat hassponsoredtheresearchandownershipofstocksandsharesorotherpecuniaryinterests,suchaspatents relatedtotheresearch.[52]Unitsthatrecruitresearchparticipantsmightbepaidapercapitafeeforeverypatient enrolled,whichcanbegreaterthantheexpensesinvolved.[53]Manypotentialfinancialsourcesofconflictsof interest,suchasindustryfundingforeducationalevents,travelorgifts,areincreasinglyrecognizedbothwithin thecontextofdailyclinicalpracticeandresearch.[54]However,otherpotentialconflictsareinherenttothe researchsetting.Anexampleisthatmedicalresearchers'statusandfutureresearchincomeisdependentonthe successoftheirresearch.[55] Identificationofapotentialconflictofinterestisnotsynonymouswithhavinganactualconflictofinterestorpoor researchpractice.Potentialconflictsofinterestareextremelycommon,andthemostimportantquestionsare whethertheyhavebeenrecognizedandhowtheyhavebeendealtwith.[56]Amainmechanismfordealingwith potentialconflictsofinterestisopendisclosure.[56]Intheprocessofcriticallyappraisingaresearcharticle,one importantstepistocheckforadeclarationaboutthesourceoffundingforthestudyand,ifapotentialconflictof interesthadbeenidentifiedforastatementabouthowthisconflictwasmanaged.Forexample,theresearchers mightstatespecificallythatthesponsoringagencyhadnoinputintotheresearchprotocol,dataanalysisor interpretationofthefindings.Manyjournalsnowroutinelyrequireauthorstodeclareanypotentialfinancialor otherconflictsofinterestwhenanarticleissubmitted.Thereadermustthendecidewhetherthedeclaredfactors areimportantandmighthaveinfluencedthevalidityofthestudy'sfindings.

Conclusions
Criticalappraisalisasystematicprocessthroughwhichthestrengthsandweaknessesofaresearchstudycan beidentified.Thisprocessenablesthereadertoassessthestudy'susefulnessandwhetheritsfindingsare trustworthy.Themostimportantcomponentofcriticalappraisaliscarefulassessmentofthestudydesign however,othersteps,suchasevaluationofthestatisticalmethodsused,interpretationofthefindingsand potentialconflictsofinterestarealsoessential.Finally,considerationoftheimportanceoftheresearchtoone's ownpatientswillhelpcliniciansidentifythemostrelevant,highqualitystudiesavailabletoguidetheirclinical practice.

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CLICKHEREforsubscriptioninformationaboutthisjournal.

KeyPoints
Criticalappraisalisasystematicprocessusedtoidentifythestrengthsandweaknessesofaresearch article

Criticalappraisalprovidesabasisfordecisionsonwhethertousetheresultsofastudyinclinicalpractice

Differentstudydesignsarepronetovarioussourcesofsystematicbias

Designspecific,criticalappraisalchecklistsareusefultoolstohelpassessstudyquality

Assessmentsofotherfactors,includingtheimportanceoftheresearchquestion,theappropriatenessof statisticalanalysis,thelegitimacyofconclusionsandpotentialconflictsofinterestareanimportantpartof thecriticalappraisalprocess


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