Lecture 9

Lecture 9
Screening
1
Lecturer
Benjamin Lebwohl MD, MS
Assistant Professor of Medicine and
Epidemiology
Celiac Disease Center
Columbia University
BL114@columbia.edu
@BenjaminLebwohl
2
Learning objectives
• Calculate central measures in screening including
sensitivity, specificity, positive predictive value, and
negative predictive value
• Explore how these parameters change when cut-points
for screening tests are changed, and discuss the
relation between disease prevalence and
positive/negative predictive values
• Discuss the pros and cons of screening and explain why
simply detecting a disease earlier than normal may not
always be of value to the patient
• Learn how lead time and length bias can distort the
apparent effectiveness of a screening program
3
Definition
• The examination of asymptomatic people in
order to classify them as likely or unlikely to
have a certain disease.
• Attempts to answer the question:
– Can we identify disease early to minimize its
consequences?
4
Goals of Screening
• Early detection of disease to prevent progression
– Presymptomatic
– Breast cancer
– Hepatitis C, HIV
• Identification of people at risk of disease
– Prevent disease development
– Blood pressure, cholesterol
– Precancerous lesions (cervical cancer, colon cancer)
5
Types of Screening
• X-Ray
– Mammograms
– Chest CT (smokers)
– Bone density
• Clinical procedure
– Colonoscopy
– Exercise stress test
• Blood/Urine sample
– Prostate cancer
– Cholesterol
6
Screening Saves Lives
• Blood pressure, cholesterol
• Breast, cervical, colon cancer
7
The Downside
• Turns people into patients
– “Cancer scare”
– Hazards of hospitalization
• Identifies conditions (including cancers) that
may not cause ill health
• Even proven screening tests can be misused
• Just because you can screen for something
doesn’t mean you should
8
Alzheimer’s Screening
9
Alzheimer’s Screening
• “Researchers report that a spinal fluid test can
be 100 percent accurate in in identifying a
signature level of abnormal proteins in
patients with significant memory loss who
went on to develop Alzheimer’s disease.”
• “So the new results also give rise to a difficult
question: Should doctors offer, or patients
accept, commercially available spinal tap tests
to find a disease that is yet untreatable?”
10
Thyroid Cancer Screening
Ahn, et al. N Engl J Med 2014; 371:1765-1767.
11
Natural History of a Disease
Detectable
Preclinical Phase
(DPCP)
Onset Detectable Symptomatic Death

by
Screening
12
DISEASE
Yes No
Pos TP FP
TEST
Neg FN TN
13
Test Characteristics
• Sensitivity:
– The proportion of diseased individuals who have a
positive (abnormal) test
• Specificity:
– The proportion of non-diseased individuals who
have a negative (abnormal) test
14
TP
Sensitivity =
TP + FN
True Positives
=
All Diseased
TN
Specificity =
TN + FP
True Negatives
=
All Non-Diseased
15
Classification of Screening Test Results
Disease
Yes No
Pos TP FP
TEST
Neg FN TN
Sensitivity = Specificity =
TP TN
TP + FN FP +TN
16
Sensitivity vs. Specificity:
What’s More Important?
• Depends on the situation
• Can change the cutoff for “abnormal” which
can affect both
• Generally, if we increase one we decrease the
other
17
Number Screened
Ideal Situation: The Perfect Test
Non-
Cases
Cases
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Score on Screen
18
The Real World
Screening Level Set at ≥5
Number Screened
Highly Sensitive
Low Specificity
Non-
Cases Cases
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Score on Screen
19
The Real World
Screening Level Set at ≥7
Number Screened
Highly Specific
Low Sensitivity
Non-
Cases Cases
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Score on Screen
20
Multiple-stage screening
• Two-stage screening test
– 1. Screen individuals using test with high
sensitivity
– 2. Follow-up with test with high specificity
• e.g. Mammogram followed by breast biopsy
21
Positive Predictive Value
• Among patients with an abnormal (positive)
test, the proportion who have the disease
22
Positive Predictive Value:
TP
=
TP + FP
True Positives
=
All Positives
23
Rules of Thumb Re: PPV
• Often PPV is what you want to know when
you’re looking at your test results.
• Instead, you’ll have the sensitivity and
specificity.
• PPV depends on more than the sensitivity and
specificity. You need to know the prevalence
of the disease.
24
Classification of Screening Test Results
Predictive TP
TEST pos TP FP Value
(positive) TP + FP
(Screening
Survey) Predictive TN
neg FN TN Value
FN +TN
(negative)
25
DISEASE
Yes No
Pos TP FP
TEST
Neg FN TN
26
Sensitivity = 70%
Specificity = 80%
DIABETES
Yes No
Pos PPV:
BLOOD 350 1900 350/2250 =15.6%
SUGAR Neg
150 7600
500 9500 10000
27
Relationship of Disease Prevalence
to Predictive Value of a Positive Test
True Status
Case Non-Case Total
Test Sensitivity = 99% TP FP
Test Result +
- FN TN
Test Specificity = 95%
Total
28
Relationship of Disease Prevalence
to Predictive Value of a Positive Test
True Status
Case Non-Case Total
Test Sensitivity = 99%
Test Result +
TP FP
- FN TN
Test Specificity = 95%
Total
Prevalence Rate = 1% Predictive Value (positive) = 17%
Prevalence Rate = 5% Predictive Value (positive) = 51%
29
Putting it All Together
Disease
yes no
Predictive TP
Screening pos TP FP Value
(positive) TP + FP
Test
Predictive TN
neg FN TN Value
(negative) FN +TN
Sensitivity = Specificity =
TP TN
TP + FN FP +TN
30
Sensitivity, Specificity, PPV, NPV
31
• Correction:
• An article on Aug. 10 about spinal fluid tests in
Alzheimer’s research left the incorrect impression
that the test can predict the disease with 100
percent accuracy in all patients.
• Among a group of patients who had memory loss
and developed Alzheimer’s within five years,
every one had protein levels associated with the
disease five years before; it was not the case that
“every one of those patients with the proteins
developed Alzheimer’s within five years.”
32
• Sensitivity = True Positives / All Diseases
• PPV = True Positives / All positives
33
• Common
• Affects children and adults
– Can develop celiac disease at any age
• Can affect multiple organ systems outside of
the gastrointestinal tract
– Can have celiac disease and not have diarrhea
– Can have celiac disease and be overweight
• Children generally don’t “grow out of it.”
34
Classical Celiac Disease
• Abdominal distension
• Abdominal pain
• Chronic diarrhea
• Anorexia
• Weight loss
• Muscle wasting
35
Reference: A summary of NASPGHAN, AGA and WHO Guidelines
Non-Classical Celiac Disease
• Iron or folate deficiency • Short stature
• Chronic constipation • Elevated liver enzymes
• IBS • Infertility
• Dental enamel defects • Osteoporosis
• Neurological (ataxia, • Delayed puberty

neuropathy, epilepsy)
• Fatigue
36
“Silent” Celiac Disease
• Screening
– First degree relatives
– DM1
• Laboratory abnormalities
• “In retrospect…”
37
38
Most U.S. Patients With Celiac Disease
Are Undiagnosed
• Seroprevalence: 0.7%-1.0%
• Percentage undiagnosed:
– Olmsted County (2001): 95%
– Wyoming (2003): 90%
– Washington County, Maryland (1989): 89%
– NHANES (2009-2010): 83%
Rubio-Tapia, et al. Am J Gastroenterol 2012;107:1538-44.
Fasano, et al. Arch Intern Med. 2003;163:286-92 Murray, et al. Clin Gastro Hep 2003;1:19-27
Katz, et al. Am J Gastroenterol 2010; 106:1333-9 Catassi et al. Ann Med 2010; 42: 530-8
39
Diminishing Mortality Risk After Diagnosis
Logan, et al. Gastroenterology 1989 97:265-71.

40
Diagnosis
Broad Concept
Clinical Blood test Start gluten-

Biopsy
Suspicion (serology) free diet
Undiagnosed celiac disease (false negatives)

Not celiac disease (false positives)
41
Serology (Blood Test)
• Tissue Transglutaminase (TTG) IgA

– Sensitivity ~90%
– Specificity ~98%
42
Population Screening for Celiac
Disease?
• Common
• Early detection is difficult
• Sensitive and specific tests
• Effective treatment is available
• Untreated disease can lead to complications
43
Problems with Screening Everyone
• Common
44
• TTG: Sensitivity ~90%, Specificity ~98%
• Population prevalence: 1%
Celiac Not Celiac
Total
Disease Disease
TTG positive
TTG negative
Total 1000
45
Celiac Not Celiac
Total
Disease Disease
TTG positive
TTG negative
Total 10 990 1000
46
Celiac Not Celiac
Total
Disease Disease
TTG positive 9
TTG negative 1
Total 10 990 1000
47
Celiac Not Celiac
Total
Disease Disease
TTG positive 9 20
TTG negative 1 970
Total 10 990 1000
48
Celiac Not Celiac
Total
Disease Disease
TTG positive 9 20 29
TTG negative 1 970 971
Total 10 990 1000
49
• Population prevalence: 1%, PPV = 31%!
Celiac Not Celiac
Total
Disease Disease
Total 10 990 1000
50
Screening High-Risk Groups
• Population prevalence: 10%, PPV = 83%!
Celiac Not Celiac
Total
Disease Disease
Total 100 900 1000
51
• Common
52
Challenges in Determining Whether
Screening is Effective
• Length time bias
• Lead time bias
• Randomized trials and other forms of
evidence
53
Forms of Bias That Make Screening
Appear More Effective Than It Really Is
• Observation:
– Patients with screen-detected prostate cancer live
longer than patients with symptom-detected
prostate cancer
– Screen-detected cancers might be different from
non-screen-detected cancers
54
Key Concept: Length-Time Bias
55
Key Concept: Length-Time Bias
56
Length Time Bias
• Screening is more likely to detect slow-
developing disease subtypes
• Slow-developing disease subtypes often have

a better prognosis than rapid-developing
subtypes
57
• 31,567 Smokers undergoing annual CT
• 484 diagnoses of lung cancer, 85% with Stage I
• 10-year survival 88%
58
59
Key Concept: Lead Time Bias
60
• Identical twins
– Hope
– Prudence
• Both develop identical
cancers at the same time:
1990
– Hope gets screened
– Prudence does not
61
• Hope gets screened in 1995,
is diagnosed, and dies of the
cancer in 2000
– 5-year survival
• Prudence discovers she has
the cancer in 1999 and dies
of the cancer in 2000
– 1-year survival
62
• Hope appeared to live longer
as a result of screening
• All screening did was to push
the clock of diagnosis
backward.
63
Hope
Prudence
64
Eligible Population
RANDOMIZE
Screen Don’t Screen
Die from Do Not Die Die from Do Not Die

the from the the from the
Disease Disease Disease Disease
65
Easier Said Than Done
• HIP Study
– 62,000 women
– Half offered mammograms
– Half not (unaware)
– Outcome: mortality from
breast cancer
66
• HIP Study Results:
– 31 deaths in mammo group
– 52 deaths in controls
– ~40% reduction!
67
• HIP Study Problems
– Need to be free of breast cancer
at the outset
– Mammo group: ask
– Controls: ?
– Equal number should be pulled
from both arms
– 434 more were pulled from
screened group
– More preexisting breast cancer in
controls?
68
• Additional trials
– Edinburgh
– Canada
– Sweden
69
• Additional trials
– Edinburgh
– Canada
– Sweden
• 42,000 women
• No overall difference in breast
cancer mortality
• Women >55 years: 20%
reduction in breast cancer
mortality
70
My Mammogram Saved My Life
To the Editor:
Three years ago, when I was 74, a yearly screening
mammogram showed a change suggestive of breast
cancer. A biopsy led to a diagnosis of cancer. A
lumpectomy followed by radiation and medication
has kept me cancer-free. According to the new
guideline recommendations, I would have had to
wait an additional year before detection. I shudder
to think about a cancer given another year to grow
and possibly spread.
New York Times. November 6, 2015
71
My Mammogram Saved My Life(?)
• 50 year-old woman:
• Mammography decreases risk of breast cancer
death by ~20%
• 10-year risk of breast cancer: 2,990 per 100,000
• 64% (1,910) detected by mammography
• 20-year breast cancer mortality: 990 per 100,000
• Without screening: 1,240 per 100,000
• 1,240-990 = 250
Welch and Frankel. Arch Intern Med. 2011;171:2043-6.
72
death by ~20%
• 1,240-990 = 250
73
death by ~20%
• 1,240-990 = 250
74
death by ~20%
• 1,240-990 = 250
• 250/1,910 = 13%
75

76
• “In fact, a woman with screen-detected cancer
is considerably more likely not to have
benefited from screening.”
77
Colon Cancer Screening
78
79
80
Fecal Occult Blood Testing Reduces
Colorectal Cancer Mortality
Mandel, et al. NEJM

1993; 328:1365-71
81
Sigmoidoscopy vs. Colonoscopy
82
Sigmoidoscopy
Case-Control Studies Indicate Benefit
Beyond reach of sigmoidoscope Within reach of sigmoidoscope
OR 0.96 (95% CI 0.61-1.50) OR 0.41 (95% CI 0.25-0.69)
Selby, et al. N Engl J Med 1992; 326:653-7

83
Society Guidelines
Colonoscopy Sigmoidoscopy FOBT
USPSTF Acceptable Acceptable Acceptable
USMSTF/ACS Preferred Preferred Acceptable
ACG Preferred Acceptable Acceptable
NYC DOH Preferred Acceptable Acceptable
84
March 2000
Cram, et al. Arch Intern Med. 2003;163:1601-5.
85
March 2000
Cram, et al. Arch Intern Med. 2003;163:1601-5.
86
Going The Distance; The Case for True
Colorectal Cancer Screening
“I believe it is time for both government and private
insurers to provide coverage for colonoscopic screening
for all persons 50 years of age or older who are at average
risk for colorectal cancer. As many people have pointed
out, relying on flexible sigmoidoscopy is as clinically
logical as performing mammography of one breast to
screen women for breast cancer. It is time to go the
distance.”
Podolsky. N Engl J Med 2000; 343:207-8
87
NYC DOH 2003
88
Should We Go the Distance?
Sigmoidoscopy Colonoscopy
Duration 10 minutes 30+ minutes
Cost $X $5X
Preparation Enema Large volume purgative
Sedation Not required Usually required
Perforation rate 0.88/1000 1.96/1000
Frazier, et al. JAMA 1998; 284:1954-61.

Gatto, et al. JNCI 2003; 95: 230-6.
89
• Report Questions Accuracy of Colonoscopy
• The test missed just about every cancer starting
in the right side of the colon, where cancers are
harder to detect. It also missed roughly a third of
cancers arising in the left side of the colon.
• “This is a really dramatic result,” said David
Ransohoff, a gasteroenterologist at the University
of North Carolina. “It makes you step back and
worry, What do we really know?”
90
• Case-control study
• Registries in Ontario
• Hypothesis: Colonoscopy is associated with
fewer colorectal cancer deaths, but to a lesser
degree than estimated in the literature.
Baxter, et al. Ann Intern Med. 2009;150:1-8.

91
Right-Sided Versus Left-Sided Cancers
Baxter, et al. Ann Intern Med. 2009;150:1-8.
92
How Could This Be?
• Didn’t reach the cecum?
• Bowel preparation?
• Biology?
• Canada?
93
Adenoma Detection Varies Widely
Between Endoscopists
Chen and Rex. Am J Gastro 2007; 102:856-61.

94
Flat Lesions
JAMA. 2008;299:1027-35.
95
Randomized Trials of Colonoscopy
First Results
Setting Comparator
Anticipated
Biennial fecal
Spain 2021
immunochemical testing
Northern Europe
Usual care 2026
(NORDICC)
Annual fecal
US (VA) 2025
immunochemical testing
www.clinicaltrials.gov
96
While We Are Waiting…
• Cohort studies:
– Nurses’ Health Study
– Health Professionals Follow-up Study
97
• Cohort study
• Exposure = colonoscopy, sigmoidoscopy, none
• Outcome = death from colorectal cancer
N Engl J Med. 2013;369:1095-105.
98
N Engl J Med. 2013;369:1095-105.
99
• Non-randomized
– Those who underwent colonoscopy may be different
from those who did not
• Adjusted for:
– Body-mass index, smoking status, family history of
colon cancer, aspirin use, physical activity level, red-
meat intake, total caloric intake, alcohol intake, folate
intake, calcium, multivitamin use, nonsteroidal anti-
inflammatory drug use, cholesterol-lowering drug use,
and postmenopausal hormone use.
N Engl J Med. 2013;369:1095-105.
100
Colorectal Cancer Screening
• Reduces colorectal cancer mortality
• The best-proven screening methods (RCT) are
the least popular
• Colonoscopy is effective
– How much more effective compared to fecal
occult blood testing or sigmoidoscopy?
• Evidence is not the only determinant of the
adoption of screening tests
• Practice often outpaces the evidence
101
What have we learned?
• Screening at its best identifies people at early
stage or pre-disease state so as to allow for an
intervention, leaving the patient better off
• We need to unpack statements that “screening is
effective,” weighing evidence in light of:
– Lead time bias
– Length time bias
– Sensitivity, Specificity, PPV, NPV
– Proven reduction of morbidity and mortality
102
Questions?
103
Thank you!
104

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Ahn, et al. N Engl J Med 2014; 371:1765-1767.

Onset Detectable Symptomatic Death

Prevalence Rate = 1% Predictive Value (positive) = 17%

Prevalence Rate = 5% Predictive Value (positive) = 51%

• PPV = True Positives / All positives

• Chronic constipation • Elevated liver enzymes

• Dental enamel defects • Osteoporosis

• Neurological (ataxia, • Delayed puberty

Rubio-Tapia, et al. Am J Gastroenterol 2012;107:1538-44.

Logan, et al. Gastroenterology 1989 97:265-71.

Clinical Blood test Start gluten-

Undiagnosed celiac disease (false negatives)

• Tissue Transglutaminase (TTG) IgA

Total 10 990 1000

Total 10 990 1000

TTG negative 1 970

Total 10 990 1000

TTG negative 1 970 971

Total 10 990 1000

TTG negative 1 970 971

Total 10 990 1000

TTG positive 90 18 108

TTG negative 10 882 892

Total 100 900 1000

• Slow-developing disease subtypes often have

Screen Don’t Screen

Die from Do Not Die Die from Do Not Die

Welch and Frankel. Arch Intern Med. 2011;171:2043-6.

Welch and Frankel. Arch Intern Med. 2011;171:2043-6.

Mandel, et al. NEJM

Beyond reach of sigmoidoscope Within reach of sigmoidoscope

OR 0.96 (95% CI 0.61-1.50) OR 0.41 (95% CI 0.25-0.69)

Selby, et al. N Engl J Med 1992; 326:653-7

Colonoscopy Sigmoidoscopy FOBT

USPSTF Acceptable Acceptable Acceptable

USMSTF/ACS Preferred Preferred Acceptable

ACG Preferred Acceptable Acceptable

NYC DOH Preferred Acceptable Acceptable

Cram, et al. Arch Intern Med. 2003;163:1601-5.

Cram, et al. Arch Intern Med. 2003;163:1601-5.

Podolsky. N Engl J Med 2000; 343:207-8

Frazier, et al. JAMA 1998; 284:1954-61.

Baxter, et al. Ann Intern Med. 2009;150:1-8.

Baxter, et al. Ann Intern Med. 2009;150:1-8.

Chen and Rex. Am J Gastro 2007; 102:856-61.

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