2 Natural history of disease Onset ofsymptomsUsual time ofdiagnosisExposurePathologicchangesStage ofsusceptibilityStage ofsubclinicaldiseaseStage ofclinicaldiseaseStage ofrecovery,disability ordeathPRIMARYPREVENTIONSECONDARYPREVENTIONTERTIARYPREVENTION
3 A Key Assumption of Screening Programs: “Screening is the application of a test to people who are asymptomatic for the purpose of classifying a person with respect to their likelihood of having a particular disease”A Key Assumption of Screening Programs:Early detection will lead to more favorable prognosis
5 Screening, in and of itself, does not diagnose disease. Persons who test positive are referred to physicians for more detailed assessmentPhysicians determine the presence or absence of disease.Screening is one of the most practical applications of epidemiology. It’s goal is to promote health and prevent disease.
6 When is it appropriate to initiate screening programs? 1. When the disease is serious2. When the prevalence of pre-clinical disease is high3. When medical care is available and health interventions are known to be effective4. When failure to screen could be considered unethical
7 World Health Organization Criterion for Screening Is it a health problem?Is there treatment?Are there facilities in place?Is it detectable pre-clinically?Is there a suitable screening test?Is the screening test acceptable to people?Is the natural history of disease understood?Are the costs acceptable?Wilson JMG, Junger G. (1967) The principles and practice of screening for Disease. Public Health Paper 34: Geneva, Switzerland: World Health Organization
8 Screening involves: Defining the target population Organizing a deployment of public health resources, policies, and proceduresDefining the target populationSetting priorities among diseases and conditionsChoosing effective screening tests
9 It also involves: Adopting practice guidelines to local needs Assessing the effectiveness of screening procedures and programsAdopting practice guidelines to local needsDealing with controversial and conflicting guidelinesTranslating guidelines into programs through public health departments, managed-care organizations, community based coalitions, and workplace coalitions.
10 Conceptual framework relating screening at the individual, settings, and community levels BasedOrganizations(e.g. Churches)HealthDepartmentsMediaClinic- Patient- Provider- Community LiaisonWorkplacesSchoolsManaged careUniversitiesPlaces ofRecreation
11 When examining a screening test we tend to look most closely at its ValidityReproducibilityEfficacy
12 How do we judge the validity of a screening test? We compare the screening test against some “gold standard”Disease “gold standard”Test Result Present AbsentPositive true positive false positiveNegative false negative true negative
13 As a measure of the validity of the test we calculate: Sensitivity= Probability that a person having the disease is detected by the test= P (test positive | they have the disease)Specificity= Probability that a person who does not have the disease is classified that way by the test= P(test negative | they don’t have the disease)
14 Disease “gold standard” Test Result Present Absent Total Positive TP FP all who test +Negative FN TN all who test -Total All with All withoutDisease DiseaseSensitivity = TP Specificity = TNTP + FN FP + TN
15 How do we examine the reproducibility? We do the tests repeatedly in the same individualsand calculate measures of:Intrasubject Variation (Table 4-7 in Gordis)Interobserver Variation (Figure 4-12 in Gordis)Overall Percent AgreementKappa Statistic
16 For a measure of the efficacy of the test we use . . . Positive Predictive Value= Probability that someone who tests positive for the disease will actually have the disease= P (have disease | positive test result)Negative Predictive Value= P (don’t have disease | negative test result)
17 Disease “gold standard” Test Result Present Absent Total Positive TP FP all who test +Negative FN TN all who test -Total All with All withoutDisease DiseasePositive predictive value = TP / TP + FPNegative predictive value = TN / TN + FN
18 if the prevalence then PPV One of the reasons Positive Predictive Value is used as a measure of efficacy is because it depends on the prevalence of the diseaseFor a given screening test with sensitivity fixed at X% and specificity fixed at Y%,if the prevalence then PPVor
19 For example, for a screening test with sens=99% and spec=95% (Gordis, 1996) DiseasePrev Test Present Absent Total PPV1% %,405 9,406 =99/594Totals , ,0005% %,025 9, =495/970Totals , ,000
20 What if we want to screen for a quantitative risk factor? Blood cholesterol levels Heart DiseasePlasma Glucose levels DiabetesCognitive function DementiaBody Mass Index ObesityBlood pressure Hypertension
21 “Disease Cutpoint” for screening For quantitative tests, we have to think about screening a little differentlyNotDiseasedFalse PositivesTrue NegativesRisk factor levelTrulyDiseasedFalse NegativesTrue PositivesRisk factor level“Disease Cutpoint” for screening
22 So what would happen if we lowered the cut off? NotDiseasedFalse PositivesTrue NegativesTrulyDiseasedFalse NegativesTrue Positives“Disease Cutpoint”
23 Some notable features of sensitivity and specificity for a quantitative test: Lowering the cutpoint for the screening test willtrue positives sensitivitytrue negatives specificityAnd of course, increasing the cutpoint will have the exact opposite effect.
24 Given that there will be trade-offs between sensitivity and specificity, how do we decide which “errors” are more costly?1. Failing to detect some true cases because of lower sensitivityor2. Misclassifying some people as diseased because of lower specificity
25 It depends . . . On the prevalence of the disease On the severity of the diseaseOn the potential fatality of the diseaseOn how good the test isOn the acceptability of the test to people
26 What’s the most appropriate cutpoint? (What if it’s a marker for a lethal disease?What its just a health indicator?)
27 What are other strategies for dealing with this tradeoff? Use parallel tests- here a positive result on any one test defines the person as a probable caseUse serial tests- here a positive result on a first test are re- evaluated on a second test- individuals must test positive on both tests to be considered a probable case.
28 Biases when evaluating a screening program There are three possible sources of bias when evaluating a screening program that may result in a false picture of its efficacy:1. Volunteer bias2. Lead time bias3. Length time bias
29 Biases when evaluating a screening program 1. Compliance (volunteer) bias: Volunteers for screening are generally more health conscious/concerned than the general population, apt to assume greater responsibility for their own care, hence, more likely to comply with therapy.
30 Biases when evaluating a screening program 2. Lead time biasLead time is the amount of time by which the diagnosis was advanced due to screening. Lead time bias means that survival may erroneously appear to be increased among screen-detected cases simply because the diagnosis was made earlier in the course of the disease.
31 Fig. 1. —Natural history of disease Fig. 1.—Natural history of disease. Diagram illustrates that preclinical phase begins at onset and ends when signs or symptoms develop. Clinical phase then starts, ending with death. Detectable preclinical phase (DPCP) begins when disease is detectable by a test. Detection (X) during DPCP advances time of diagnosis by duration of lead time.
32 Fig. 2.—Lead-time bias. Diagram shows that, with screening, time of diagnosis is advanced by lead time provided by positive test result. If earlier diagnosis has no effect on time of death from disease, then survival with testing is equal to survival without testing plus lead time.
33 Biases when evaluating a screening program 3. Length time biasLess aggressive forms of a disease are more likely to be picked up in a screening program because they have a longer detectable pre-clinical phase. Less aggressive forms of disease usually have better survival.
34 Fig. 3.—Diagram shows how probability of detection is related to rate of disease progression. Length of each arrow represents length of detectable preclinical phase, from initial detectability to clinical diagnosis (Dx). Testing at a single moment detects four slowly progressive cases but only two rapidly progressive cases. Cases not detected by test (thin arrows) are diagnosed clinically either before or after time of testing. Thick arrows indicate detected cases.
36 Prostate cancerIt is the second most common form of cancer among men in the United States.It is also the second leading cause of cancer deaths.American Cancer Society estimates that 179,300 new cases of prostate cancer were diagnosed in 1999 and 37,000 men died in 1999.This cancer is most common among men 65 years and older.
37 Prostate cancer At all ages, African American men have the highest incidence of PCA in the worlddiagnosed with the disease at later stagesdie of prostate cancers at higher rates
38 Incidence of Prostate Cancer Recently, we’ve been better able to detect prostate cancer and hence our estimates of its incidence have increased
39 Death rates for Prostate Cancer Death rates for African American men is twice what it is for White men.
40 Age-dependent Incidence and Death Rates Incidence of PCA appears to level off above 70 yrsbut the death rate becomes exponentially worse at that age.
41 Early Detection The benefits of early detection of prostate cancer are thought to be the same as for any cancer.However,Little is know about how to prevent the diseaseScientific evidence is lacking about whether screening reduces deathsEvidence is lacking about whether current treatments really prolong men’s lives.
42 Two commonly used methods for detecting prostate cancer 1. Digital rectal examination (DRE)This has been used for years. . . But its ability to detect PCA is limitedIt can’t detect some small tumorsIt can’t distinguish between benign tumors and cancer
43 2. Prostate-specific antigen (PSA) test PSA is an enzyme that increases with age and because of prostate abnormalitiesIts now used widely but medical consensus hasn’t been reached on its utilityIt also cannot distinguish between benign and cancerous tumors.
44 What are the treatment alternatives? Radical prostatectomyRadiation therapyWatchful waiting
45 Criterion Prostate Cancer Is it a health problem? Yes Is there treatment? ProbablyAre there facilities in place? YesIs it detectable pre-clinically? YesIs there a suitable screening test? YesIs the screening test acceptable? YesIs the disease understood? PartiallyAre the costs acceptable? PossiblyIs continuous screening set up? PrematureMeyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; (8):
46 Test result Present Absent Total Positive 197 1169 1366 Data from American Cancer Society’s National Prostate Cancer Detection Project and the European Randomized Study of Screening for Prostate CancerProstate CancerTest result Present Absent TotalPositiveNegativeTotalPositive test result = a PSA level >4ng/ml and DRE evidenceFalse negatives detected by biopsy after transurethal ultrasonography yielded abnormal findings.Meyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; (8):
47 Data from Canadian National Breast Screening Study Breast Cancer Test result Present Absent TotalPositive ,230 3,372Negative ,324 16,339Total , ,711Positive test result = a suspicious finding by mammogram and/or physical examFalse negatives are those in whom breast cancer was discovered in 1st yr follow-upMeyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; (8):
48 Comparison of Breast and Prostate Cancer Prostate Breast Cancer CancerSensitivity,%Specificity, %Positive test, %Prevalence, %Positive predictivevalue, %Meyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; (8):
49 Other issues related to Screening Programs: Evaluating the effectiveness of the programDefining High Risk subgroups- Those subgroups for whom the prevalence of asymptomatic disease is expected to be higherEthical considerations- Who should be offered the test?- Who should have access to the results?
50 Selected Examples of Prevention Effectiveness Annual US % of personsPrevention Undesired Incidence without Prevention Economic at Risk CoveredType* Outcome Intervention Method % Effectiveness Analysis by MethodPrimary Measles ,000, Vaccination $16.85 per By age 2, 50-80%; case prevented by age 6, 98%Secondary Breast cancer , Mammography $45K to $165K perdeaths screening year of life savedTertiary Blindness from , Retinal screening, $100 per year ofDiabetes treatment vision saved* Primary prevention = directed at susceptible persons before they develop a particular disease (risk factor reduction);Secondary prevention = directed at persons who are symptomatic but who have developed biologic changes (early detectionand treatment);Tertiary prevention = directed at preventing disability in persons who have symptomatic disease (prevent complications andrehabilitation).SOURCE: Thacker et. Al. (1994)
51 Mammography Risk Relative Percentage Group Health Cooperative of Puget Sound’s Breast Cancer Risk Algorithm and Screening ProtocolMammography Risk Relative PercentageFrequency Level Risk-Level Criteria Risk WomenAnnualEvery 2 YearsEvery 3 YearsNot Recommended1234Previous breast cancer or atypia on biopsy results; at least 2 first-degree relatives with breast cancerOne first-degree relative with breast cancer; >50 years of age and >2 MRF’s>50 years of age and >1 MRF; or >50 years of age and > MRF<50 years of age and no MRF4-141.01156617Source: Taplin et al. (1990)
52 Conditions for Which Screening Is Recommended, USPSTF 1996 Health Outcome Test(s) Populations(s) Age Group (years)HIVHbgSS/PKU/HypothyroidismAnemiaLead poisoningRubellaTuberculosisHearingVisionLabHgb/PhenylalanineT4&TSHHgb/HctBlood leadPPD--HR2/HR3General/GeneralgeneralHR1/HR/P(female)HR7General (female)HR1/HR3/HR6/HR7General0-10/11+Birth/BirthBirth0-1011-24, 25-6465+/0-24/25-6465+0-10, 65+Source: U.S. Preventive Services task Force [USPSTF] (1996)
53 More Conditions for Which Screening Is Recommended Health Outcome Test(s) Populations(s) Age Group (years)ObesityCVD/HBPCVDInjury/Liver diseaseColorectal cancerBreast cancerCervical cancerChlamydiaGonorrheaSyphilisHeight/WeightBlood pressureCholesterolAlcohol overuseFecal Occult Blood TestSigmoidoscopyMammography/Clinical Breast ExamPap SmearLabGeneralGeneral/HR6General/HR4HR2HR1/HR9All25-64/65+11+25+50+ (female)11+ (female)11-24/11-6411-24, 25-6411-64/65+Source: U.S. Preventive Services task Force [USPSTF] (1996)