2/1/2011natural history; population screening1 natural history of disease / population screening...
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2/1/2011 Natural history; population screening 1
Natural history of disease / population screening
Principles of Epidemiology for Public Health (EPID600)
Victor J. Schoenbach, PhD home page
Department of EpidemiologyGillings School of Global Public Health
University of North Carolina at Chapel Hill
www.unc.edu/epid600/
2/3/2004 2
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
9/24/2001 3
What not to say in your job interview
“Herb Greenberg, a leading authority on work-related 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 4
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 5
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.”
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• 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
Disease natural history and prevention
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•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
Disease natural history & population screening
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World Health Organization:
“a state of complete physical, mental, [and] social well-being and not merely the absence of disease or infirmity”
Phenomenon of health: what is health?
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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)
Phenomenon of disease: what is disease?
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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)
Phenomenon of disease: what is disease?
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• Disease is a process that unfolds over time
• Natural history – sequence of developments from earliest pathological change to resolution of disease or death
Phenomenon of disease: natural history
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• Induction – time to disease initiation
• Incubation – time to symptoms (infectious disease)
• Latency – time to detection (for non-infectious disease) or to infectiousness
Phenomenon of disease: natural history
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• Induction – time to disease initiation
• Incubation – time to symptoms (infectious disease)
• Latency – time to detection (for non-infectious disease) or to infectiousness
Phenomenon of disease: natural history
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• Induction – time to disease initiation
• Incubation – time to symptoms (infectious disease)
• Latency – time to detection (for non-infectious disease) or to infectiousness
Phenomenon of disease: natural history
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Natural history of coronary heart disease
“Spontaneous atherosclerosis”
“Lipid lesion”Fibrointimal
lesionPlaque growth,
occlusion
Chronic minimal injury (blood flow, CHL, smoking, infection?) (youth?)
Accumulation of lipids and monocytes, toxic products, platelet adhesion(adolescence)
Migration & proliferation of smooth muscle cells
(adulthood)
Disruption
thrombi
(adulthood)
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Natural history of coronary heart disease
“Spontaneous atherosclerosis”
“Lipid lesion”Fibrointimal
lesionPlaque growth,
occlusion
Chronic minimal injury (blood flow, CHL, smoking, infection?) (youth?)
Accumulation of lipids and monocytes, toxic products, platelet adhesion(adolescence)
Migration & proliferation of smooth muscle cells
(adulthood)
Disruption
thrombi
(adulthood)
1/9/2007 Natural history; population screening 17
Natural history of coronary heart disease
“Spontaneous atherosclerosis”
“Lipid lesion”Fibrointimal
lesionPlaque growth,
occlusion
Chronic minimal injury (blood flow, CHL, smoking, infection?) (youth?)
Accumulation of lipids and monocytes, toxic products, platelet adhesion(adolescence)
Migration & proliferation of smooth muscle cells
(adulthood)
Disruption
thrombi
(adulthood)
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Natural history is central to screening
Pre-detectableDetectable, preclinical
ClinicalDisability or death
Possible detection via screening
Clinical detection
Age: 35 45 55 65 75
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“application of a test to asymptomatic people to detect occult disease or a precursor state” (Alan Morrison, Screening in Chronic Disease, 1985)
Population screening
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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
Population screening
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1. Suitable disease
2. Suitable test
3. Suitable program
4. Good use of resources
Requirements for a screening program
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• Serious consequences if untreated
• Detectable before symptoms appear
• Better outcomes if treatment begins before clinical diagnosis
1. Suitable disease
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• Detect during pre-symptomatic phase
• Safe
• Accurate
• Acceptable, cost-effective
2. Suitable test
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• Reaches appropriate target population
• Quality control of testing
• Good follow-up of positives
• Efficient
3. Suitable program
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• Cost of screening tests
• Cost of follow-up diagnostic tests
• Cost of treatment
• Benefits versus alternatives
4. Good use of resources
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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.. . .
Screening for Breast CancerU.S. Preventive Services Task ForceDecember 4, 2009
2/1/2011 Natural history; population screening 28
David ShabtaiFaculty 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.
Revisiting the USPSTF Breast Cancer Screening Guidelines: Ethics, and Patient Responsibilities
2/1/2011 Natural history; population screening 29
September 10, 2010
Recommended Weekend ReadingBy 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.”
Mammography Wars
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September 29, 2010
Mammogram Benefit Seen for Women in Their 40sBy 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.
Who should get a mammogram?
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Newsweek
The Mammogram HustleThere 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.
What should we pay for?
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By Julie SteenhuysenCHICAGO | 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.
New U.S. analysis backs annual breast screening
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“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.”
AJR: USPSTF mammo recommendations could cost 6,500 lives yearly
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Survival time after diagnosis – lead time
Pre-detectable Detectable, preclinical Clinical Disability
or death
Possible detection via screening
Clinical detection
Age: 35 45 55 65 75
Lead time
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Survival time must increase > lead time
Pre-detectable Undetected(no screening)
Clinicaldiagnosis &treatment
Disability or death
Age: 35 45 55 65 75
Pre-detectable Early detect, diagnosis, &
treatment
Monitoringfor recurrence ?
Survival time after diagnosis
Lead time
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Slowly progressing diseases are easier to detect by screening
Pre-detectable
Clinical diagnosis,treatment
Disability or death
Age: 35 45 55 65 75
Pre-detectable Detectable,pre-clinical
Clinical diagnosis &
treatment
Disabilityor death
Survival time after diagnosis
Survival time after diagnosis
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Early detection may over-diagnose
Pre-detectable Undetected(no screening)
Mild or no symptoms
Favorableoutcome
Age: 35 45 55 65 75
Pre-detectable Early detect, diagnosis, &
treatment
Monitoringfor recurrence
Favorableoutcome
Survival time after diagnosis
Survival time after dx
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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]
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Reliability
Repeatability – get same result• Each time• From each instrument• From each rater
If don’t know correct result, then can examine reliability only.
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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
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Validity: 1) Sensitivity
Probability (proportion) of correct classification of cases
Cases found / all cases
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Validity: 2) Specificity
Probability (proportion) of correct classification of noncases
Noncases identified / all noncases
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O
OO
OO
O
O
OO
O
O
Remember this slide? 2 cases / month
O
9/16/2003 Natural history; population screening 44
O
OO
OO
O
O
O
O
O
Pre-detectable preclinical clinical old
OO
OO
O
9/16/2003 Natural history; population screening 45
O
OO
OOO
O
O
OO
O
O
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OO
O
O
O OO
OO
Pre-detectable pre-clinical clinical old
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O
OO
OOO
O
O
OO
O
O
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OO
O
O
O OO
OO
What is the prevalence of “the condition”?
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Sensitivity of a screening test
Probability (proportion) of correct classification of detectable, pre-clinical cases
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O
OO
OOO
O
O
OO
O
O
Pre-detectable pre-clinical clinical old (8) (10) (6) (14)
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OO
O
O
O OO
OO
9/10/2002 Natural history; population screening 49
O
OO
OOO
O
O
OO
O
O
Correctly classifiedSensitivity: ––––––––––––––––––––––––––– Total detectable pre-clinical (10)
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OO
O
O
O OO
OO
9/10/2002 Natural history; population screening 50
Specificity of a screening test
Probability (proportion) of correct classification of noncases
Noncases identified / all noncases
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O
OO
OOO
O
O
OO
O
O
Pre-detectable pre-clinical clinical old (8) (10) (6) (14)
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OO
O
O
O OO
OO
9/10/2002 Natural history; population screening 52
O
OO
OOO
O
O
OO
O
O
Correctly classifiedSpecificity: ––––––––––––––––––––––––––––– Total non-cases (& pre-detect) (162 or 170)
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OO
O
O
O OO
OO
9/10/2002 Natural history; population screening 53
Truepositive
Truenegative
Falsepositive
Falsenegative
Sensitivity = True positives
All cases
a + c b + d
= a
a + c
Specificity = True negatives All non-cases
= db + d
a + b
c + d
True Disease Status
Cases Non-cases
Positive
Negative
ScreeningTest
Results
a d b
c
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True Disease Status
Cases Non-cases
Positive
Negative
ScreeningTest
Results
a d
1,000 b
c60
Sensitivity = True positives
All cases
200 20,000
= 140200
Specificity = True negatives All non-cases
= 19,00020,000
1,140
19,060
140
19,000
=
= 70%
95%
1/9/2007 Natural history; population screening 55
Interpreting test results: predictive value
Probability (proportion) of those tested who are correctly classified
Cases identified / all positive tests
Noncases identified / all negative tests
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Truepositive
Truenegative
Falsepositive
Falsenegative
PPV = True positives
All positives
a + c b + d
= a
a + b
NPV = True negatives All negatives
=d
c + d
a + b
c + d
True Disease Status
Cases Non-cases
Positive
Negative
ScreeningTest
Results
a d b
c
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True Disease Status
Cases Non-cases
Positive
Negative
ScreeningTest
Results
a d
1,000 b
c60
PPV = True positives
All positives
200 20,000
= 1401,140
NPV = True negatives All negatives
= 19,00019,060
1,140
19,060
140
19,000
=
= 12.3%
99.7%
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Positive predictive value, Sensitivity, specificity, and prevalence
Prevalence (%) PV+ (%) Se (%) Sp (%) 0.1 1.4 70 95
1.0 12.3 70 95
5.0 42.4 70 95
50.0 93.3 70 95
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Example: Mammography screening of unselected women
Disease status
Cancer No cancer Total Positive 132 985 1,117 Negative 47 62,295 62,342
Total 179 63,280 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
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Effect of Prevalence on Positive Predictive Value
PV+ = 64%
PV+ = 88%
Sensitivity = 93%, Specificity = 92%
Surgical biopsy (“gold standard”) Cancer No cancer Prev.
Without palpable mass in breast
Fine needle Positive 14 8 13%aspiration Negative 1 91
With palpable mass in breast
Fine needle Positive 113 15 38%aspiration Negative 8 181
See http://www.meddean.luc.edu/lumen/MedEd/ipm/IPM1/Biostats/diagnostic_test_example1_Solutions1011.pdf
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What is used as a “gold standard”
1. Most definitive diagnostic procedure e.g. microscopic examination of a tissue specimen
2. Best available laboratory teste.g. polymerase chain reaction (PCR)
for HIV virus
3. Comprehensive clinical evaluatione.g. clinical assessment of arthritis
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Main concepts1. Requirements for a screening program2. Concept of natural history – possible biases include lead time, “length”, over-diagnosis3. Reliability (repeatable) – can occur by chance4. Validity (correct) – sensitivity, specificity5. Sensitivity and specificity relate to the detectable pre-clinical stage of the disease6. Predictive value – the population perspective on disease detection