Principles of Screening

William C. Black, M.D.Dartmouth-Hitchcock Medical Center

William.Black@Hitchcock.org

www.dhmc.org/goto/chest-imaging

Definition

Screening can be defined as the systematic testing

of individuals who are asymptomatic with respect to

some target disease. The purpose of screening is to

prevent, interrupt, or delay the development of

advanced disease in the subset with a pre-clinical

form of the target disease through early detection

and treatment.

Hillman et al. JACR 2004;1(11):861-864

Screening vs Diagnosis

Asymptomatic

Test non-diagnostic

Low prevalence

Non-patients Patients

Symptomatic

Test diagnostic

High prevalence

Signs orSymptoms

Detectableby Test

Onset ofDisease

Death fromDisease orOther causes

PRECLINICAL CLINICAL

DPCP

Timeline of Disease

Critical Point

The point in the natural history of disease

before which therapy is more effective.

Death fromDisease orOther causes

Signs orSymptoms

Detectableby Test

Onset ofDisease

DPCP

Screening Effective

Critical Point

Death fromDisease orOther causes

Signs orSymptoms

Detectableby Test

Onset ofDisease

DPCP

Screening Ineffective

Critical Point

Death fromDisease orOther causes

Signs orSymptoms

Detectableby Test

Onset ofDisease

DPCP

Screening Unnecessary

Critical Point

Survival vs

Stage

Mountain CF. Chest 1986;89(suppl):225-233.

Mayo Clinic ProjectScreened(CXR + SC)

Control(Usual)

Subjects1 4,618 4,593

Incident cases 206 160

% resectable 46 31

% five-year survival 31 13

Lung cancer deaths

Relative risk2 (95%CI)1 91 prevalent cases and 1631 others excluded before randomization2 based on cumulative lung cancer mortality at eleven year

Mayo Clinic ProjectScreened(CXR + SC)

Control(Usual)

Subjects1 4,618 4,593

Incident cases 206 160

% resectable 46 31

% five-year survival 31 13

Lung cancer deaths 122 115

Relative risk2 (95%CI) 1.06 (0.82-1.36)1 91 prevalent cases and 1631 others excluded before randomization2 based on cumulative lung cancer mortality at eleven year

Knox PA

• Hamartoma

SPN 4-10mm

• Scoble

Screen Detected Cases ELCAP

Stage < 10 mm 11-20 mm 20+ mm

I 13 8 2

II 1 0 0

III 1 0 2

Henschke et al. Lancet 1999;354(9173):99-105.

Screen Detected Cases ELCAP

Stage < 10 mm 11-20 mm 20+ mm

I 13 8 2

II 1 0 0

III 1 0 2

Estimated five-year survival 80% vs 13% in SEER

Henschke et al. Lancet 1999;354(9173):99-105.

•Lead time bias

•Length bias

•Overdiagnosis bias

Biases of Early Detection

Death fromDisease

WITH TEST

Signs or symptoms

Positive test

LEADTIME

SURVIVAL

WITHOUT TEST

SURVIVAL

Lead Time Bias

TIME

Slowly progressive

Rapidly progressive

Length BiasTEST

TIME

Slowly progressive

Rapidly progressive

Length BiasTEST

TIME

Slowly progressive

Rapidly progressive

Length BiasTEST

Tumor Histology ELCAP

• Adenocarcinoma (18)

• Bronchioloalveolar carcinoma (3)

• Mixed squamous adenocarcinoma (3)

• Squamous cell carcinoma (1)

• Atypical carcinoid (1)

25 Prevalent Cases

Henschke et al. Lancet 1999;354(9173):99-105.

The diagnosis of a condition that

would not have become clinically

significant had it not been detected.

Overdiagnosis

Growth Rate of Lung Cancer

• Median DT 181 days

• 22% DT >= 465 days

• 94% >= 1 yr grow 0.5-3.0 cm

Winer-Muram. Radiology 2002;223(3):798-805.

Lung Ca Screening in Japan

Subjects Lungcancers

Rate(1000)

Smokers 6295 29 4.6

NonSmokers 7491 31 4.1

Total 13786 60 4.4

Sone et al. Br J Cancer 2001; 84(1): 25-32.

•Falsely increases sensitivity of test

•Falsely increases PPV of test

•Falsely increases incidence

•Falsely improves stage distribution

•Falsely improves case survival

•Does not decrease pop mortality

Effects of Overdiagnosis

Comparisons of Survival

are Invalid and Biased

Deaths from disease

Person-years of observation

Population-based Mortality

•Correlation

•Case-control

•Cohort

Observational Studies

Selection Bias

If higher, then bias against screening

If lower, then bias in favor of screening

Those screened at different risk than

those not screened.

Randomized Clinical Trial

To ensure that observed differences in

outcome depend only on the interven-

tions under investigation and not on

other factors that affect outcome.

Screening RCTEnroll screen

eligible subjects

Randomize

Screen Arm Control Arm

Assess EndpointsAssess Endpoints

Benefits from Screening

• Anxiety about dz (TN)

• Morb & mort from dz

• Morb & mort from rx

lobectomy vs pneumonectomy

Harms from Screening

• Direct effect of test (radiation)

• Anxiety about dz (FP)

• Morb & mort from work-up

• Overdiagnosis

Patient Population

• High risk for preclinical disease

• No clinical signs or symp of disease

• Willing and able to undergo screening or not

• Willing and able to undergo workup and rx

• Willing and able to undergo follow-up

Endpoints

• Deaths from target disease

• Deaths from any cause

• Stage of target disease at dx

• Adverse events

• Quality of life

• Resource utilization

Sample Size Determination

• Death rate from disease

• Duration of follow-up

• Effectiveness of screening

• Power and significance level

• Compliance in each arm

Sample Size

Smokers60-69

All40-69

Screen vs no screenRRR 50%Compliance 100%

2,072 12,669

Screen vs no screenRRR 20%Compliance 80%

44,807 274, 042

(one-sided),

•Not affected by COD misclassification

•Puts screening in perspective

•Insensitive measure of efficacy

All Cause Mortality

Generalizability

• Participants

• Screening tests and radiologists

• Treatment and supportive care

•Compliance

•Statistical power

•Ascertainment Bias

•Generalizability

RCT Limitations

True positive, effective

True positive, ineffective

True negative

False positive

False negative

Overdiagnosis

Major benefit. Death postponed,

morbidity decreased

Knowledge vs longer dx & rx

Reassurance

Harm. Work up

Possibly delayed dx

Moderate to major harm. False

labeling and rx

Cancer Screening Outcomes and Values

Summary

• Diseases are dynamic processes

• The evaluation of screening is difficult

• Survival statistics are inappropriate and biased

• RCT is most valid design, but has limitations.

References

1. Bach PB, Niewoehner DE, Black WC. Screening for lung cancer: the guidelines. Chest 2003;123(1 Suppl):83S-88S.2. Black WC. Overdiagnosis: An underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 2000;92(16):1280-2.3. Black WC, Haggstrom DA, Welch HG. All-cause mortality in randomized trials of cancer screening. J Natl Cancer Inst 2002;94(3):167-73.4. Black WC, Welch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. New England Journal of Medicine 1993;328(17):1237-43.5. Black WC, Welch HG. Screening for disease. AJR. American Journal of Roentgenology 1997;168(1):3-11.6. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhn JR, et al. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer 1991;67(suppl):1155-1164.7. Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening [see comments]. Lancet 1999;354(9173):99-105.8. Hillman BJ, Black WC, D'Orsi C, Hauser B, Smith R. The Appropriateness of Employing Imaging Screening Technologies - Report of the Methods Committee of the ACR Task Force on Screening Technologies. JACR 2004;1(11):861-864.9. Morrison AS. The natural history of disease in relation to measures of disease frequency. In: Screening in chronic disease. 2nd ed. New York: Oxford University Press; 1992. p. 21-42.10. Mountain CF. A new international staging system for lung cancer. Chest 1986;89(suppl):225S-233.11. Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: their application to multislice CT screening for pulmonary and colorectal cancers. AJR Am J Roentgenol 2001;176(6):1357-62.12. Sone S, Li F, Yang ZG, Honda T, Maruyama Y, Takashima S, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer 2001;84(1):25-32.13. Welch HG, Schwartz LM, Woloshin S. Are increasing 5-year survival rates evidence of success against cancer? JAMA 2000;283(22):2975-8.14. Winer-Muram HT, Jennings SG, Tarver RD, Aisen AM, Tann M, Conces DJ, et al. Volumetric growth rate of stage I lung cancer prior to treatment: serial CT scanning. Radiology 2002;223(3):798-805.

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This web site and contents is provided for informational and educational purposes only and is not intended as medical advice nor is it intended to create any physician-patient relationship. Please remember that this information should not substitute for a visit or a consultation with a health care provider. The views or opinions expressed in the resources provided do not necessarily reflect those of Dartmouth-Hitchcock Medical Center or the Radiological Society of North America.

Financial Disclosure

I do not have nor have I had during the previous 12 months a relationship with a company or organization whose products or services are directly related to the subject matter of this presentation.

William C. Black, M.D.