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Transcript
Principles of Epidemiology for Public Health (EPID600)
Natural history of disease /
population screening
Victor J. Schoenbach, PhD home page
Department of Epidemiology
Gillings School of Global Public Health
University of North Carolina at Chapel Hill
www.unc.edu/epid600/
2/1/2011
Natural history; population screening
1
SHE shouldn’ts
(courtesy of www.flylady.net
# 8: SHE's shouldn't let themselves get too tired –
Last week I was going over some homeschooling
with my 11yo DD when I realized I hadn't seen or
heard my fast-crawling 13-month old DD in a
while. I said, "Anyone know where the baby is?"
My older daughter just looked at me and said,
"Mom?" Lo and behold, I'm nursing the baby! - in
Colorado
2/3/2004
2
What not to say in your job interview
“Herb Greenberg, a leading authority on workrelated personality testing, keeps a list of the
dumbest things people have told his corporate
clients during recent job interviews.” (Cheryl Hall,
Knight Ridder, Herald-Sun, 1/26/2003: F2)
(Greenberg is the 73-year-old chief executive
officer of Caliper, in Princeton NJ)
9/24/2001
3
Have you ever thought of saying …
• “I will definitely work harder for you than I did for
my last employer.”
• “I don’t think I’m capable of doing this job, but I
sure would like the money.”
• “Do you know of any companies where I could
get a job I would like better than this one?”
9/24/2001
4
Have you ever thought of saying …
• “I’m quitting my present job because I hate to
work hard.”
• An apology for yawning “I usually sleep until my
soap operas are on.”
9/24/2001
5
Disease natural history and prevention
• Knowledge of the natural history of
disease is fundamental for effective
prevention
• Levels of prevention:
- Primary – prevent the disease
[Primordial – prevent the risk factors]
- Secondary – early detection and Rx
- Tertiary – treat and minimize disability
2/1/2011
Natural history; population screening
6
Disease natural history & population screening
•Phenomenon of disease
- What is disease?
- Natural history of disease
•Requirements for screening programs
• Detection of disease
- Sensitivity
- Specificity
• Interpreting diagnostic & screening tests
- Predictive value
2/1/2011
Natural history; population screening
7
Phenomenon of health: what is health?
World Health Organization:
“a state of complete physical, mental,
[and] social well-being and not merely
the absence of disease or infirmity”
2/1/2011
Natural history; population screening
8
Phenomenon of disease: what is disease?
Difficult to define, e.g.:
“a type of internal state which is either an
impairment of normal functional ability–that
is, a reduction of one or more functional
abilities below typical efficiency–or a
limitation on functional ability caused by
environmental agents”
(C. Boorse, What is disease? In: Humber M, Almeder RF, eds. Biomedical ethics
reviews. Humana Press, Totowa NJ, 1997, 7-8 (quoted in Temple et al., 2001)
1/9/2007
Natural history; population screening
9
Phenomenon of disease: what is disease?
Difficult to define, e.g.:
“a state that places individuals at
increased risk of adverse consequences”
(Temple LKF et al., Defining disease in the genomics era. Science 3 Aug
2001;293:807-808)
9/10/2002
Natural history; population screening
10
Phenomenon of disease: natural history
• Disease is a process that unfolds over time
• Natural history – sequence of
developments from earliest pathological
change to resolution of disease or death
9/10/2002
Natural history; population screening
11
Phenomenon of disease: natural history
• Induction – time to disease initiation
• Incubation – time to symptoms (infectious
disease)
• Latency – time to detection (for noninfectious disease) or to infectiousness
9/10/2002
Natural history; population screening
12
Phenomenon of disease: natural history
• Induction – time to disease initiation
• Incubation – time to symptoms (infectious
disease)
• Latency – time to detection (for noninfectious disease) or to infectiousness
9/10/2002
Natural history; population screening
13
Phenomenon of disease: natural history
• Induction – time to disease initiation
• Incubation – time to symptoms (infectious
disease)
• Latency – time to detection (for noninfectious disease) or to infectiousness
1/29/2008
Natural history; population screening
14
Natural history of coronary heart disease
“Spontaneous
atherosclerosis”
Chronic
minimal injury
(blood flow,
CHL, smoking,
infection?)
(youth?)
1/9/2007
“Lipid lesion”
Accumulation of
lipids and
monocytes,
toxic products,
platelet
adhesion
(adolescence)
Fibrointimal
lesion
Plaque growth,
occlusion
Migration &
Disruption
proliferation of
thrombi
smooth
muscle cells
(adulthood)
(adulthood)
Natural history; population screening
15
Natural history of coronary heart disease
“Spontaneous
atherosclerosis”
Chronic
minimal injury
(blood flow,
CHL, smoking,
infection?)
(youth?)
1/9/2007
“Lipid lesion”
Accumulation of
lipids and
monocytes,
toxic products,
platelet
adhesion
(adolescence)
Fibrointimal
lesion
Plaque growth,
occlusion
Migration &
Disruption
proliferation of
thrombi
smooth
muscle cells
(adulthood)
(adulthood)
Natural history; population screening
16
Natural history of coronary heart disease
“Spontaneous
atherosclerosis”
Chronic
minimal injury
(blood flow,
CHL, smoking,
infection?)
(youth?)
1/9/2007
“Lipid lesion”
Accumulation of
lipids and
monocytes,
toxic products,
platelet
adhesion
(adolescence)
Fibrointimal
lesion
Plaque growth,
occlusion
Migration &
Disruption
proliferation of
thrombi
smooth
muscle cells
(adulthood)
(adulthood)
Natural history; population screening
17
Natural history is central to screening
Pre-detectable
Age:
35
Detectable,
preclinical
45
Possible detection
via screening
9/10/2002
Clinical
55
65
Disability
or death
75
Clinical
detection
Natural history; population screening
18
Population screening
“application of a test to asymptomatic people
to detect occult disease or a precursor state”
(Alan Morrison, Screening in Chronic Disease, 1985)
9/10/2002
Natural history; population screening
19
Population screening
Immediate objective of a screening test – to
classify people as being likely or unlikely of
having the disease
• Ultimate objective: to reduce mortality and
morbidity
9/10/2002
Natural history; population screening
20
Test that can help save your life
2/1/2011
Natural history; population screening
21
Requirements for a screening program
1. Suitable disease
2. Suitable test
3. Suitable program
4. Good use of resources
9/10/2002
Natural history; population screening
22
1. Suitable disease
• Serious consequences if untreated
• Detectable before symptoms appear
• Better outcomes if treatment begins
before clinical diagnosis
9/10/2002
Natural history; population screening
23
2. Suitable test
• Detect during pre-symptomatic phase
• Safe
• Accurate
• Acceptable, cost-effective
9/10/2002
Natural history; population screening
24
3. Suitable program
• Reaches appropriate target population
• Quality control of testing
• Good follow-up of positives
• Efficient
9/10/2002
Natural history; population screening
25
4. Good use of resources
• Cost of screening tests
• Cost of follow-up diagnostic tests
• Cost of treatment
• Benefits versus alternatives
9/10/2002
Natural history; population screening
26
Screening for Breast Cancer
U.S. Preventive Services Task Force
December 4, 2009
Summary of Recommendations
•The USPSTF recommends biennial screening mammography for women
aged 50 to 74 years.
Grade: B recommendation.
•The decision to start regular, biennial screening mammography before the
age of 50 years should be an individual one and take patient context into
account, including the patient's values regarding specific benefits and harms.
Grade: C recommendation.
•The USPSTF recommends against teaching breast self-examination (BSE).
Grade: D recommendation.
...
2/1/2011
Natural history; population screening
27
Revisiting the USPSTF Breast Cancer Screening
Guidelines: Ethics, and Patient Responsibilities
David Shabtai
Faculty Peer Reviewed
In a bold move, the U.S. Preventive Services Task Force recently changed
their breast cancer screening guidelines – recommending beginning
screening at age 50 and even then only every other year until age 75. Bold,
because the Task Force members are certainly aware of the media circus that
ensued when in 1997, an NIH group issued similar guidelines, prompting
comparisons to Alice in Wonderland.
2/1/2011
Natural history; population screening
28
Mammography Wars
September 10, 2010
Recommended Weekend Reading
By NATASHA SINGER
“Can we trust doctors’ recommendations on cancer screening,
given that the medical profession has a vested financial interest in
treating patients? That is one of the questions posed in a
provocative article this week in The New England Journal of
Medicine that looks at the fallout last year after a government panel
recommended that women start having mammograms later in life
and less frequently.”
2/1/2011
Natural history; population screening
29
Who should get a mammogram?
September 29, 2010
Mammogram Benefit Seen for
Women in Their 40s
By GINA KOLATA
Researchers reported Wednesday that
mammograms can cut the breast cancer death
rate by 26 percent for women in their 40s.
But their results were greeted with skepticism
by some experts who say they may have
overestimated the benefit.
2/1/2011
Natural history; population screening
30
What should we pay for?
Newsweek
The Mammogram Hustle
There is no evidence digital mammograms improve cancer
detection in older women. But thanks to political pressure,
Medicare pays 65 percent more for them.
This story was reported and written by Center for Public Integrity.
2/1/2011
Natural history; population screening
31
New U.S. analysis backs annual breast
screening
By Julie Steenhuysen
CHICAGO | Wed Jan 26, 2011 12:26pm EST
(Reuters) - A new analysis of evidence used by
a U.S. advisory panel to roll back breast cancer
screening guidelines suggests it may have
ignored evidence that more frequent
mammograms save more lives, U.S. researchers
said on Tuesday.
2/1/2011
Natural history; population screening
32
AJR: USPSTF mammo recommendations
could cost 6,500 lives yearly
“The U.S. Preventive Services Task Force (USPSTF) “chose to
ignore the science available to them” and brought about “potential
damage to women’s health” in its 2009 recommendations for more
limited mammography screening, costing an estimated 6,500 deaths
in women each year, a study published in the February issue of the
American Journal of Roentgenology concluded.”
2/1/2011
Natural history; population screening
33
Survival time after diagnosis – lead time
Detectable,
preclinical
Pre-detectable
Age:
35
45
Clinical
55
65
Disability
or death
75
Lead time
Possible detection
via screening
9/10/2002
Clinical
detection
Natural history; population screening
34
Survival time must increase > lead time
Undetected
(no screening)
Pre-detectable
Clinical
diagnosis &
treatment
Disability
or death
Survival time after diagnosis
Early detect,
diagnosis, &
treatment
Pre-detectable
Monitoring
for recurrence
?
Lead time
Age:
9/10/2002
35
45
55
Natural history; population screening
65
75
35
Slowly progressing diseases are easier to
detect by screening
Clinical
diagnosis,
treatment
Predetectable
Disability
or death
Survival time after diagnosis
Detectable,
pre-clinical
Pre-detectable
Clinical
diagnosis &
treatment
Disability
or death
Survival time after diagnosis
Age:
9/10/2002
35
45
55
Natural history; population screening
65
75
36
Early detection may over-diagnose
Undetected
(no screening)
Pre-detectable
Mild or no
symptoms
Favorable
outcome
Survival time after diagnosis
Early detect,
diagnosis, &
treatment
Pre-detectable
Monitoring
for recurrence
Favorable
outcome
Survival time after dx
Age:
1/9/2007
35
45
55
Natural history; population screening
65
75
37
Screening test
Reliable – get same result each time
Validity – get the correct result
Sensitive – correctly classify cases
Specificity – correctly classify non-cases
[screening and diagnosis are not identical]
9/10/2002
Natural history; population screening
38
Reliability
Repeatability – get same result
• Each time
• From each instrument
• From each rater
If don’t know correct result, then can
examine reliability only.
9/16/2003
Natural history; population screening
39
Reliability
• Percent agreement is inflated due to
agreement by chance
• Kappa statistic considers agreement
beyond that expected by chance
• Reliability does not ensure validity, but
lack of reliability constrains validity
9/10/2002
Natural history; population screening
40
Validity: 1) Sensitivity
Probability (proportion) of
correct classification of cases
/
Cases found all cases
2/1/2011
Natural history; population screening
41
Validity: 2) Specificity
Probability (proportion) of
correct classification of noncases
/
Noncases identified all noncases
9/10/2002
Natural history; population screening
42
Remember this slide? 2 cases / month
OO

OO
O

O


O

OOO
O

O


9/16/2003
Natural history; population screening
43
Pre-detectable
preclinical
clinical
old
OO

OO
O

O
O

O

O
O

O
O
OO

O


9/16/2003
Natural history; population screening
44
Pre-detectable
pre-clinical
clinical
old
O
O O
OO

O
O
OO O O

O
O
O O

O O
O O

O
O
O
O
O

OOO
O O

O
O O
O
O

O O
O
O

9/16/2003
Natural history; population screening
45
What is the prevalence of “the condition”?
O
O O
OO

O
O
OO O O

O
O
O O

O O
O O

O
O
O
O
O

OOO
O O

O
O O
O
O

O O
O
O

1/29/2008
Natural history; population screening
46
Sensitivity of a screening test
Probability (proportion) of
correct classification of detectable, preclinical cases
9/10/2002
Natural history; population screening
47
Pre-detectable
(8)
pre-clinical
(10)
clinical
(6)
old
(14)
O
OO
O O

O
O
OO O O

O
O O
O

O O
O O

O
O
O
O
O

OOO
O O

O
O
O O
O

O O
O
O

9/10/2002
Natural history; population screening
48
Correctly classified
Sensitivity: –––––––––––––––––––––––––––
Total detectable pre-clinical (10)
O
OO
O O

O
O
OO O O

O
O O
O

O O
O O

O
O
O
O
O

OOO
O O

O
O
O O
O

O O
O
O

9/10/2002
Natural history; population screening
49
Specificity of a screening test
Probability (proportion) of
correct classification of noncases
Noncases identified / all noncases
9/10/2002
Natural history; population screening
50
Pre-detectable
(8)
pre-clinical
(10)
clinical
(6)
old
(14)
O
OO
O O

O
O
OO O O

O
O O
O

O O
O O

O
O
O
O
O

OOO
O O

O
O
O O
O

O O
O
O

2/1/2011
Natural history; population screening
51
Correctly classified
Specificity: –––––––––––––––––––––––––––––
Total non-cases (& pre-detect) (162 or 170)
O
OO
O O

O
O
OO O O

O
O O
O

O O
O O

O
O
O
O
O

OOO
O O

O
O
O O
O

O O
O
O

9/10/2002
Natural history; population screening
52
True Disease Status
Screening
Test
Results
Positive
Cases
Non-cases
True
positive
False
positive
a+b
True
negative
c+d
a b
c d
Negative
False
negative
a+c
b+d
a
True positives
=
Sensitivity =
a+c
All cases
True negatives
d
Specificity =
=
All non-cases
b+d
9/10/2002
Natural history; population screening
53
True Disease Status
Screening
Test
Results
Positive
Cases
Non-cases
140
1,000
1,140
19,000
19,060
a b
c d
Negative
60
200
20,000
True positives
140
Sensitivity =
=
= 70%
All cases
200
Specificity = True negatives = 19,000 = 95%
20,000
All non-cases
5/26/2008
Natural history; population screening
54
Interpreting test results: predictive value
Probability (proportion) of those tested who
are correctly classified
Cases identified / all positive tests
Noncases identified / all negative tests
1/9/2007
Natural history; population screening
55
True Disease Status
Screening
Test
Results
Positive
Cases
Non-cases
True
positive
False
positive
a+b
True
negative
c+d
a b
c d
Negative
False
negative
a+c
b+d
True positives
a
PPV =
=
All positives
a+b
True negatives
d
NPV =
=
All negatives
c+d
9/10/2002
Natural history; population screening
56
True Disease Status
Screening
Test
Results
Positive
Cases
Non-cases
140
1,000
1,140
19,000
19,060
a b
c d
Negative
60
200
20,000
True positives
140
PPV =
=
= 12.3%
All positives
1,140
19,000
NPV = True negatives =
= 99.7%
19,060
All negatives
1/9/2007
Natural history; population screening
57
Positive predictive value,
Sensitivity, specificity, and prevalence
Prevalence (%)
0.1
PV+ (%)
1.4
Se (%) Sp (%)
70
95
1.0
12.3
70
95
5.0
42.4
70
95
50.0
93.3
70
95
1/29/2008
Natural history; population screening
58
Example: Mammography screening of unselected women
Disease status
Positive
Negative
Total
Cancer
132
47
179
No cancer
985
62,295
63,280
Total
1,117
62,342
63,459
Prevalence = 0.3% (179 / 63,459)
Se = 73.7% Sp = 98.4% PV+ = 11.8% PV– = 99.9%
Source: Shapiro S et al., Periodic Screening for Breast Cancer
1/9/2007
Natural history; population screening
59
Effect of Prevalence on Positive Predictive Value
Sensitivity = 93%, Specificity = 92%
Surgical biopsy (“gold standard”)
Cancer No cancer Prev.
Without palpable mass in breast
Fine needle
aspiration
Positive
Negative
14
1
8
13%
91 PV+ = 64%
113
8
15
38%
181 PV+ = 88%
With palpable mass in breast
Fine needle
aspiration
Positive
Negative
See http://www.meddean.luc.edu/lumen/MedEd/ipm/IPM1/Biostats/diagnostic_test_example1_Solutions1011.pdf
2/2/2011
Natural history; population screening
60
What is used as a “gold standard”
1. Most definitive diagnostic procedure
e.g. microscopic examination of a tissue
specimen
2. Best available laboratory test
e.g. polymerase chain reaction (PCR)
for HIV virus
3. Comprehensive clinical evaluation
e.g. clinical assessment of arthritis
9/10/2002
Natural history; population screening
61
Main concepts
1. Requirements for a screening program
2. Concept of natural history – possible biases include
lead time, “length”, over-diagnosis
3. Reliability (repeatable) – can occur by chance
4. Validity (correct) – sensitivity, specificity
5. Sensitivity and specificity relate to the detectable
pre-clinical stage of the disease
6. Predictive value – the population perspective on
disease detection
9/16/2003
Natural history; population screening
62
Have you ever thought of saying …
• “My resume might make it look like I’m a job
hopper. But I want you to know that I never left
any of those jobs voluntarily.”
• “What job am I applying for anyway?”
9/24/2001
63