Principles of Screening
William C. Black, M.D.Dartmouth-Hitchcock Medical Center
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.
Disclaimer
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.
Top Related