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Principles of Screening
William C. Black, M.D.
Dartmouth-Hitchcock Medical Center
[email protected]cock.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
Non-patients
Patients
Asymptomatic
Symptomatic
Test non-diagnostic
Test diagnostic
Low prevalence
High prevalence
Timeline of Disease
PRECLINICAL
CLINICAL
DPCP
Onset of
Disease
Detectable
by Test
Signs or
Symptoms
Death from
Disease or
Other causes
Critical Point
The point in the natural history of disease
before which therapy is more effective.
Screening Effective
DPCP
Onset of
Disease
Detectable
by Test
Critical Point
Signs or
Symptoms
Death from
Disease or
Other causes
Screening Ineffective
DPCP
Onset of
Disease
Detectable
by Test
Critical Point
Signs or
Symptoms
Death from
Disease or
Other causes
Screening Unnecessary
DPCP
Onset of
Disease
Detectable
by Test
Signs or
Symptoms
Death from
Disease or
Other causes
Critical Point
Survival vs Stage
Mountain CF. Chest 1986;89(suppl):225-233.
Mayo Clinic Project
1
Subjects
Incident cases
% resectable
% five-year survival
Lung cancer deaths
Relative risk2 (95%CI)
1
Screened
Control
(CXR + SC)
(Usual)
4,618
4,593
206
46
31
160
31
13
91 prevalent cases and 1631 others excluded before randomization
2 based on cumulative lung cancer mortality at eleven year
Mayo Clinic Project
1
Subjects
Incident cases
% resectable
% five-year survival
Lung cancer deaths
Relative risk2 (95%CI)
1
Screened
Control
(CXR + SC)
(Usual)
4,618
4,593
206
160
46
31
31
13
122
115
1.06 (0.82-1.36)
91 prevalent cases and 1631 others excluded before randomization
2 based on cumulative lung cancer mortality at eleven year
Knox PA
• Hamartoma
SPN 4-10mm
• Scoble
Screen Detected Cases ELCAP
Henschke et al. Lancet 1999;354(9173):99-105.
Stage
I
< 10 mm
11-20 mm 20+ mm
13
8
2
II
1
0
0
III
1
0
2
Screen Detected Cases ELCAP
Henschke et al. Lancet 1999;354(9173):99-105.
Stage
I
< 10 mm
11-20 mm 20+ mm
13
8
2
II
1
0
0
III
1
0
2
Estimated five-year survival 80% vs 13% in SEER
Biases of Early Detection
•Lead time bias
•Length bias
•Overdiagnosis bias
Lead Time Bias
Signs or
symptoms
WITHOUT TEST
Death from
Disease
SURVIVAL
WITH TEST Positive
test
SURVIVAL
LEAD
TIME
Length Bias
Rapidly
progressive
TEST
Slowly
progressive
TIME
Length Bias
Rapidly
progressive
TEST
Slowly
progressive
TIME
Length Bias
Rapidly
progressive
TEST
Slowly
progressive
TIME
Tumor Histology ELCAP
25 Prevalent Cases
• Adenocarcinoma (18)
• Bronchioloalveolar carcinoma (3)
• Mixed squamous adenocarcinoma (3)
• Squamous cell carcinoma (1)
• Atypical carcinoid (1)
Henschke et al. Lancet 1999;354(9173):99-105.
Overdiagnosis
The diagnosis of a condition that
would not have become clinically
significant had it not been detected.
Growth Rate of Lung Cancer
Winer-Muram. Radiology 2002;223(3):798-805.
• Median DT 181 days
• 22% DT >= 465 days
• 94% >= 1 yr grow 0.5-3.0 cm
Lung Ca Screening in Japan
Subjects Lung
Rate
cancers (1000)
Smokers
6295
29
4.6
NonSmokers
7491
31
4.1
13786
60
4.4
Total
Sone et al. Br J Cancer 2001; 84(1): 25-32.
Effects of Overdiagnosis
•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
Comparisons of Survival
are Invalid and Biased
Population-based Mortality
Deaths from disease
Person-years of observation
Observational Studies
•Correlation
•Case-control
•Cohort
Selection Bias
Those screened at different risk than
those not screened.
If higher, then bias against screening
If lower, then bias in favor of screening
Randomized Clinical Trial
To ensure that observed differences in
outcome depend only on the interventions under investigation and not on
other factors that affect outcome.
Enroll screen
eligible subjects
Screening RCT
Randomize
Screen Arm
Control Arm
Assess Endpoints
Assess 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
a=0.05(one-sided), b=0.20
Smokers
60-69
All
40-69
Screen vs no screen
RRR 50%
Compliance 100%
2,072
12,669
Screen vs no screen
RRR 20%
Compliance 80%
44,807
274, 042
All Cause Mortality
•Not affected by COD misclassification
•Puts screening in perspective
•Insensitive measure of efficacy
Generalizability
• Participants
• Screening tests and radiologists
• Treatment and supportive care
RCT Limitations
•Compliance
•Statistical power
•Ascertainment Bias
•Generalizability
Cancer Screening Outcomes and Values
True positive, effective
Major benefit. Death postponed,
morbidity decreased
True positive, ineffective
Knowledge vs longer dx & rx
True negative
Reassurance
False positive
Harm. Work up
False negative
Possibly delayed dx
Overdiagnosis
Moderate to major harm. False
labeling and rx
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 physicianpatient 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.