Screening in Disease Detection

1. Screening in Disease Detection

2. Natural history of disease Onset of symptoms Usual time of diagnosis Exposure Pathologic changes Stage of subclinical disease Stage of recovery, disability or death Stage of clinical disease Stage of susceptibility PRIMARY PREVENTION SECONDARY PREVENTION TERTIARY PREVENTION

3. “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 assessment • Physicians 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 serious 2. When the prevalence of pre-clinical disease is high 3. When medical care is available and health interventions are known to be effective 4. 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: • Organizing a deployment of public health resources, policies, and procedures • Defining the target population • Setting priorities among diseases and conditions • Choosing effective screening tests

9. It also involves: • Assessing the effectiveness of screening procedures and programs • Adopting practice guidelines to local needs • Dealing with controversial and conflicting guidelines • Translating 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 Community Community Based Organizations (e.g. Churches) Health Departments Media Clinic - Patient - Provider - Community Liaison Workplaces Schools Managed care Universities Places of Recreation

11. When examining a screening test we tend to look most closely at its Validity Reproducibility Efficacy

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 Absent Positive true positive false positive Negative 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 withAll without DiseaseDisease Sensitivity = TP Specificity = TN TP + FNFP + TN

15. How do we examine the reproducibility? We do the tests repeatedly in the same individuals and calculate measures of: Intrasubject Variation (Table 4-7 in Gordis) Interobserver Variation (Figure 4-12 in Gordis) Overall Percent Agreement Kappa 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 = Probability that someone who tests positive for the disease will actually have the disease = 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 TNall who test - Total All with All without Disease Disease Positive predictive value = TP / TP + FP Negative predictive value = TN/ TN + FN

18. One of the reasons Positive Predictive Value is used as a measure of efficacy is because it depends on the prevalence of the disease For a given screening test with sensitivity fixed at X% and specificity fixed at Y%, if the prevalence then PPV or if the prevalence then PPV

19. For example, for a screening test with sens=99% and spec=95% (Gordis, 1996) Disease Prev Test Present Absent Total PPV 1% + 99 495 59417% - 1 9,405 9,406 =99/594 Totals 100 9,900 10,000 5% + 495 475 97051% - 5 9,025 9,030 =495/970 Totals 500 9,500 10,000

20. What if we want to screen for a quantitative risk factor? Blood cholesterol levels Heart Disease Plasma Glucose levels Diabetes Cognitive function Dementia Body Mass Index Obesity Blood pressure Hypertension

21. For quantitative tests, we have to think about screening a little differently Not Diseased False Positives True Negatives Risk factor level Truly Diseased False Negatives True Positives Risk factor level “Disease Cutpoint” for screening

22. So what would happen if we lowered the cut off? Not Diseased False Positives True Negatives Truly Diseased False Negatives True Positives “Disease Cutpoint”

23. Some notable features of sensitivity and specificity for a quantitative test: Lowering the cutpoint for the screening test will true positives sensitivity true negatives specificity And 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 sensitivity or 2. Misclassifying some people as diseased because of lower specificity

25. It depends . . . On the prevalence of the disease On the severity of the disease On the potential fatality of the disease On how good the test is On 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 case Use 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 bias • 2. Lead time bias • 3. 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 bias Lead 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. 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 bias Less 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.

35. Prostate Cancer Example

36. Prostate cancer It 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. http://www.cdc.gov/cancer/prostate/prostate.htm

37. Prostate cancer • At all ages, African American men • have the highest incidence of PCA in the world • diagnosed with the disease at later stages • die of prostate cancers at higher rates • http://www.cdc.gov/cancer/prostate/prostate.htm

38. Incidence of Prostate Cancer Recently, we’ve been better able to detect prostate cancer and hence our estimates of its incidence have increased http://www.cdc.gov/cancer/prostate/prostate.htm

39. Death rates for Prostate Cancer Death rates for African American men is twice what it is for White men. http://www.cdc.gov/cancer/prostate/prostate.htm

40. Age-dependent Incidence and Death Rates Incidence of PCA appears to level off above 70 yrs but the death rate becomes exponentially worse at that age. http://www.cdc.gov/cancer/prostate/prostate.htm

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 disease • Scientific evidence is lacking about whether screening reduces deaths • Evidence 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 limited • It can’t detect some small tumors • It 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 abnormalities • Its now used widely but medical consensus hasn’t been reached on its utility • It also cannot distinguish between benign and cancerous tumors.

44. What are the treatment alternatives? Radical prostatectomy Radiation therapy Watchful waiting

45. Criterion Prostate Cancer Is it a health problem? Yes Is there treatment? Probably Are there facilities in place? Yes Is it detectable pre-clinically? Yes Is there a suitable screening test? Yes Is the screening test acceptable? Yes Is the disease understood? Partially Are the costs acceptable? Possibly Is continuous screening set up? Premature Meyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; 1998 159(8):968-972

46. Data fromAmerican Cancer Society’s National Prostate Cancer Detection Projectand theEuropean Randomized Study of Screening for Prostate Cancer Prostate Cancer Test result Present Absent Total Positive 197 1169 1366 Negative 29 5828 5857 Total 226 6997 7223 Positive test result = a PSA level >4ng/ml and DRE evidence False negatives detected by biopsy after transurethal ultrasonography yielded abnormal findings. Meyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; 1998 159(8):968-972

47. Data fromCanadian National Breast Screening Study Breast Cancer Test result Present Absent Total Positive 142 3,230 3,372 Negative 15 16,324 16,339 Total 226 19,5554 19,711 Positive test result = a suspicious finding by mammogram and/or physical exam False negatives are those in whom breast cancer was discovered in 1st yr follow-up Meyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; 1998 159(8):968-972

48. Comparison of Breast and Prostate Cancer Prostate Breast Cancer Cancer Sensitivity,% 87.2 90.4 Specificity, % 83.3 83.5 Positive test, % 18.9 17.1 Prevalence, % 3.1 0.8 Positive predictive 14.4 4.2 value, % Meyer F, Fradet Y. Clinical basics:Prostate Cancer:4. Screening. Can Med Assoc J; 1998 159(8):968-972

49. Other issues related to Screening Programs: • Evaluating the effectiveness of the program • Defining High Risk subgroups • - Those subgroups for whom the prevalence of asymptomatic disease is expected to be higher • Ethical considerations • - Who should be offered the test? • - Who should have access to the results?

50. Selected Examples of Prevention Effectiveness Annual US % of persons Prevention Undesired Incidence without Prevention Economic at Risk Covered Type* Outcome Intervention Method % Effectiveness Analysis by Method Primary Measles 4,000,000 Vaccination 95-98 $16.85 per By age 2, 50-80%; case prevented by age 6, 98% Secondary Breast cancer 50,000 Mammography 20-70 $45K to $165K per 15-38 deaths screening year of life saved Tertiary Blindness from 24,000 Retinal screening, 50 $100 per year of 60-80 Diabetes 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 detection and treatment); Tertiary prevention = directed at preventing disability in persons who have symptomaticdisease (prevent complications and rehabilitation). SOURCE: Thacker et. Al. (1994)