TH RD ED T o NClinicalEpidemiologyTHEESSENTIALSRobert H. Fletcher, M.D., M.sc.ProfessorDepartment of AmbulatoryCare andPreventionHarvard Medical School:,"'''o'''',""oL',1505oL,----,t"-,Iillibfl-50 40 30 20 10 0 10 20 30 4050+5101510Ul

1lo'0 E::lZUnderestimate OverestimateERROR(beats/min)Figure2.2. Observer variability. Error in reportingfetal heart rateaccordingtowhether thetruerate, determinedby electronicmonitor, is withinthe normal range,low, or high. (Redrawn from DayE, Maddern L, Wood C. Auscultation of foetalheartrate: anassessment of its error andsignificance. BrMedJ1968;4:422-424.)VPDs, similar to other patients studied(3). VPDs per hour variedfromlessthan20 to 380 during a 3-day period, according to day andtime of day. Theauthors concluded: "TodistinguishareductioninVPDfrequencyattribut-able to therapeutic intervention rather than biologic or spontaneous variationalonerequiredagreaterthan83%reductioninVPDfrequencyif onlytwo24-hour monitoring periodswere compared."Vilriation also arises because of differences amongpeople. Biologic dif-ferences amongpeople predominate in many situations. For example, sev-eral studies haveshownthathighbloodpressureonsingle, casual mea-28 CLINICALEPIDEMIOLOGY400Day 1NoonDay3oL . ; ; = - : : : : - : : : : ~ ~ ~ : : : : ; ; ~ ~ ~ Day2Midnight 6 A.M.200300100~~C0.>'0~1:E"zFigure 2.3. Biologic variability. The number of ventricular premature depolarizations(VPDs) for one untreatedpatient on 3 consecutive days, (RedrawnfromMorganrothJ, MichelsonEL, HorowitL LN,Josephson ME, Pearlman AS, DunkmanWB, Limita-tionsof routinelong-termelectrocardiographicmonitoring toassessventricularec-topicfrequency, Circulation1978;58:408-414,)surements, althoughsubject toall otherformsofvariation, isrelated tosubsequent cardiovascular disease.TOTALVARIATIONTheseveral sourcesorvariationarecumulative. Figure2.4i11ustratesthisforthemeasurement of bloodpressure. Variationfrommeasurementcontributes relativelylittle, althoughit coversas muchas a 12mmHgrangeamongvariousobservers. Ontheotherhand,each patient'sbloodpressure varies a great dealfrommoment to moment throughout the day,sothe, more ofwhomhave adv,lnceddisease.BIASSometimesthesensitivityandspecificityofatest arenot establishedindependentlyofthemeansbywhichthetruediagnosis is established,leading to abiasedassessmentofthetest'sproperties. This mayoccur in56 CLINICAL EPIDEMIOLOGYseveral ways, Asalreadypointedout, ifthetest isevaluatedusingdataobtainedduringthecourseof aclinical evalu.;'ltionofpatientssuspectedof having the diseasein question, a positive test may prompt the cliniciantocontinue pursuing thediagnosis, increasing thelikelihoodthatthedis-easewill be found, Onthe other hand, a negative test may cause theclinician to abandon further testing, making it more likely that the disease,if present, will be missed.In other situations, thetest result may be part oftheinformationusedtoestablishthediagnosis, or conversely, the results of the test maybeinterpreted takingother clinical information or the final diagnosis intoaccount.Radiologistsarefrequentlysubject to thiskindof bias whentheyreadx-rays. Because x-rayinterpretation is somewhat subjective, it is easyto be influenced by the clinical information provided. All clinicians experi-encethe situation of havingx-rays overreadbecause of aclinical impres-sion, or conversely, of goingback over oldx-rays in which afindingwasmissedbecause a clinical event wasnot known atthetime, andtherefore,attentionwasnotdirectedtotheparticularareainthex-ray. Becauseofthesebiases, someradiologists prefertoreadx-rays twice, first withoutandthenwiththe clinical information. All of these biases tendto increasethe agreementbetween thetest andthe standI--w"'>40 0-0.1-0020wa:0.01/5 1/10 1/50 1/100PREVALENCE1/1000 1/10,000Figure 3.8. Positive predictive value according to sensitivity, specificity, and-prevalence of disease.Current effortstoprevent transmissionof acquiredimmunodeficiencysyndrome (AIDS) through bloodproducts is another example of the effectof disease prevalence onpositivepredictive value.Example A blood test forantibodies to human immunodeficiency (HIV)isusedto screen blooddonors. At one cutoff point, the sensitivityis97,8/" andthespl:'cificityis90.4%. In1985, thepositivepredictivevalueofthetest was estimatedfromthe prevalence of infectiouslUlits to be no morethan 1/10,000. Thus there wouldbe 9,250 false-positivetest results for everytrue-positiveresult (8). Almost 10,000unitswouldhavetobediscardedorinvestigatedfurther toprevent onetransfusionof contaminatedblood. Theauthors concludedthat, forthis emotionally charged subject, "careful adher-ence to the principles of diagnostic test evaluationwill avoid expectations."But thesituationchanged. Astheprevalence of HIV infectionincreasedinthe general population, the positive predictive value of the screeningtestimproved. Ina publicationa year later, the prevalence of infected unitsamong67,190testedwas25/10,000, andat similarlevels of sensitivity andspecificity, the positive predictive value wouldbe2.5;':" much higher than afewyearsbefore(9).ESTIMATINGPREVALENCEHow can clinicians estimate theprevalence orprobability of disease ina patient to determine the predictive value of a test result? There are severalsources of infonnation: the medical literature, local databases, andclinicaljudgment. Althoughtheresultingestimateofprevalenceisseldomveryprecise, erroris not likelyto besogreat as tochangeclinicaljudgmentsCHAPTER3 ! DIAGNOSIS 61that arebasedontheestimate. Inanycase, theprocess isboundtobemoreaccuratethanimplicit judgment alone.Tn general, prevalence is more important than sensitivity andspecificityindeterminingpredictivevalue(seefig. 3.8). Onereason whythis issois that prevalence commonlyvaries over a wider range. Prevalence ofdiseasecanvaryfromafractionof apercent tonearcertaintyinclinicalsettings, depending ontheage, gender, riskfactors, andclinical findingsof the patient. Contrast the prevalence of liver disease in a healthy,youngadult who uses no drugs, illicit or otherwise, and consumes only occasionalalcohol, withthatof a jaundicedintravenous druguser. Bycurrent stan-dards, cliniciansarcnotparticularlyinterestedintestswithsensitivitiesandspecificitiesmuchbelow50'Yo, but ifbothsensitivityandspecificityare99/;" the test is consideredagreat one. Inother words, inpracticaltermssensitivityandspecificity rarely vary morethantwofold.INCREASINGTHEPREVALENCEOFDISEASEConsidering the relationship between the predictive value of atest andprevalence, it is obviously to the physician's advantage to apply diagnosticteststopatients withanincreasedlikelihood of havingthediseasebeingsought. In fact as Figure 3.8 shows, diagnostic tests aremost helpful whenthepresence of diseaseisneitherverylikely nor veryunlikely.ThereMeavarietyof waysinwhichtheprobabilityof adiseasecanbeincreasedbefore using adiagnostictest.Referral ProcessThereferral process is one of the most common ways in which theprobabilityof disease is increased. Referral to teaching hospital wards,clinics, andemergencydepartments increasesthechancethat significantdiseasewill tmderliepatients' complaints. Therefore, relativelymoreag-gressiveuse of diagnostictestsmightbe justifiedinthesesettings. Inpri-marycare practice, ontheother hand, andparticularlyamongpatientswithout complaints, thechance of findingdisease is considerably smaller,andtests shouldbe usedmore sparingly.Example Whilepracticingin amilitaryclinic, oneoftheauthorssawhundreds of people with headache, rarely ordered diagnostic tests, and neverencounteredapatient withasevere underlyingcaUSl' ofheadache. (It islUllikely that important conditions were missedbccause the clinic was virtu-.,lIy the only source of medical care for t ~ patients and proloneed follow-upwasavailable.)However, duringthefirst weekbackinamedical resi-dency,a patient visitingthehospital'semergency department because of aheadache similartothe onesmanagedin the militarywasfoundtohaveacerebellar absCl':'s!Because clinicians may work at different extremes of theprevalence spec-trum atvarious timesintheirclinicalpractices, they should bear in mind62 CLINICAL EPIDEMIOLOGYthat the intensity of diagnostic evaluation mayneedto be adjustedto suitthe specific situation.SelectedDemographic GroupsIn agivensetting,physicians can increase theyield of diagnostictestsby applying themtodemographic groups knowntobe athigherriskforadisease. 1\ manof65is 15times morelikelytohavecoronaryarterydisease asthecause of atypical chest painthanawomanof30i thustheelectrocardiographicstress test, aparticular diagnostictest for coronarydisease, is lessuseful in confirmingthediagnosisintheyounger womanthanintheolderman(10). Similarly, asickle-cell test wouldobviouslyhavea higher positive predictive value among blacks than amongwhites.Specifics of the Clinical SituationThe specifics of theclinical situationare clearly the strongest influenceonthedecisiontoordertests. Symptoms, signs, anddiseaseriskfactorsall raise or lower the probability of finding a disease. For example, a womanwithchest painis morelikelyto have coronary diseaseif shehastypicalangina and hypertension and she smokes. As a result, an abnormal electro-cardiographicstress test is morelikelytorepresent coronarydiseaseinsuch a woman than in persons with nonspecific chest pain and no coronaryriskfactors.The value of applying diagnostic teststopersons more likelytohave aparticular illnessis intuitively obvious tomost doctors. Nevertheless, withthe increasingavailabilityof diagnostic tests, it is easytoadopt a lessselective appmachwhenorderingtests. However, thelessselective theapproach, thelowertheprevalenceofthediseaseislikelytobeandthelowerwillbethepositivepredictive value ofthetest.The magnitude of this effect can be larger than most of us mightthink.Example Factors that influence the interpretation of an abnormal electro-cardiographic stress test arl:' illustrated in Figure 3.9. It shows that the positivepredictive value for coronary artery disease (CAD) associated with an abnor-maltest canvaryfrom1.7to99.8%, depending on age, symptoms, andthedegreeof abnormality of thetest.Thus an exercise test inanasymptomatic3.'i-year-old manshowing1mmSTseh'lllent depressionwill beafalse-positive test in more than 98% of cases. The same test result in a 60-year-oldmanwith typicall'mgina byhistorywill be associatedwithcoronary arterydisease in more than 90%of cases(10).Because of this effect,physicians mustinterpret similar test results dif-ferentlyin different clinical situations. A negative stress test in an asymp-tomatic35-year-oldmanmerelyconfirmsthealreadylowprobabilityofcoronary arterydisease, but apositivetest usually will be misleading if itis usedto search for unsuspected disease, as has been done among joggers,airline pilots, andbusiness executives. The opposite applies tothe 65-CHAPTER3 I DIAGNOSIS 63L::'EI 0.5-1.0mm_> 2.5mm100gOw::>80'">70w_ = ~60~00-'"50iiloa: a:40"0w"-30"!::20'" 0..100AgeSymptomPrevalenceofCAD(%)30-39None1.g60-69 60-69None Atypicalangina60-69Typicalangina94.3Figure 3.9. Effect of disease prevalence onpositive predictive value of a diagnostictest. Probability of coronary artery diseaseinmen according to age, symptoms, anddepression of $T segment on electrocardiogram. (Data fromDiamond GA, ForresterJS. Analysis of probability as an aid in the clinical diagnosis of coronary artery disease.NEngl J Med1979;300:1350-1358.)year-oldmanwithtypical angina. Inthiscase, thetestmay behelpful inconfirming disease but not in excluding disease.The testis mostusefulinintermediate situations, in which prevalence isneither very highnor verylow. For example, a60-year-oldmanwithatypical chest p'1J l3ooKs, 1989,Coodman SN, lJerlin JA, The usc of predicted confidence intervJIs when pbnning expnim'mtsJndthemibuseof powerwheninte'lwetingAnnInternMed'1994;'12'1:2(KI-206,HilnkylA, Lil'mcln.IIJnd A. If nothinggoes wrongis everythingright? InterpretingzeronUlllerators. JA1I.1'\ Hl'nnekens CH, Bllring IF. inmedicine. Boston: Little, Brown&Co., 1987,Ingelfinger JA. r>-l%tdkr F. Thihodeau I,A, VI/Me Jll, I:)ioslatistics inclinical medicine, NewYork: Ma"milklll, 1983,Moses 1 StatistiGll concepts fundamental to inVl'stigJtion,; NEngl J Med1985;312:890H97.]\iegclman I{K, Hirsch RP SI.udyingand stLldytesting a tebt. 2nd "d. Boston; Little,Brown&Co., 1989,RothmanKI A bhowof confidence. NFllgi J MedI97fl;299:B62 1361.Youngl\ilJ, BresnitzEA, StromilL. Sample sizenomogramsfor interpreting negative clinic,,1/\nnInternMed1'JH3;9'J;24B-251.10STUDYINGCASESEacii caseliasits lesson-alessonwhichmaybebut isnotalwayslearned.-SirWilliam OslerMost medical knowledge has emanated from the intensive study of sickpatients. The exhaustedbut engrossed physicianat the bedside of thefebrilechild, chininhand, isa f