How do we delay disease progress once it has started?
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Transcript of How do we delay disease progress once it has started?
How do we delay disease progress once it has started?
Epidemiology matters: a new introduction to methodological foundations
Chapter 13
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
3Epidemiology Matters – Chapter 13
1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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Screening
Screening is the process in which we use a test to determine whether an individual likely has a particular health indicator or not or is likely to develop a particular health indicator or notScreening is not the same as diagnosis; screening tests give us information about whether the disease is likely to be presentA screening test assesses the presence of an underlying marker that is associated with outcome of interest
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Screening, examples
Women receive regular screening tests beginning in young adulthood for cervical cancer (Pap smear)
Physicians assess blood pressure and cholesterol as screening tools for the development of cardiovascular disease
Women use home pregnancy tests to screen for presence of an embryo or fetus
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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When to screen
We screen for disease when we have the opportunity to reduce costs and risk
associated with diagnoses on large proportions of at-risk individuals
1. We screen for health indicators that affect population health principally, not for
rare diseases (although there are exceptions for rare diseases screen in utero)
2. There should be sufficient time between biological onset of disease and
appearance of signs and symptoms of the disease exist so that screening could
detect the presence of the disease earlier than it would come to clinical
attention
3. There should be available treatment for the disease so that early detection
improves the lives of affected
4. Screening tests should be cheaper and less invasive than best available
diagnostic tool
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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Screening test evaluation
1. Sensitivity2. Specificity3. Positive predictive value4. Negative predictive value
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Screening test evaluation
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Screening test evaluation, example
Questions: Should all men be tested for prostate cancer with the new screening tool? High rates of prostate cancer among Farrlandian men New test characterizes level of antigen in blood
demonstrated to be associated with prostate cancer Test is inexpensive and requires only a blood specimen
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Screening test evaluation, example
240 men with confirmed incident diagnoses of prostate cancer
2,500 men confirmed free of prostate cancer Measure antigen level for all men
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Screening test evaluationantigen among sample
Antigen
D- D+
Mean level of antigen is higher among men with prostate cancer
Distributions of antigen overlap
Between 37 and 56 ng/mL - both diseased and non-diseased men
A cut-off if typically declared within this uncertain range
Individuals above the cut-off are screening positive or below, screen negative
Cut-off is often largely arbitrary and informs performance of screening test
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Screening test evaluationsensitivity and specificity
To assess the validity of a screening tool in establishing the presence of disease we compare with a gold standard
Sensitivity: Whether individuals with disease are correctly identified by the screening test as having the disease
Specificity: Whether individuals without the disease are correctly identified by the screening test as not having the disease
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Screening test evaluationcut-off
False Positives
ScreensNegative
Screens Positive
D+
Screening Cut-Off
D-
Antigen
Lowest value on the antigen distribution of men with prostate cancer = 38 ng/mL.
Cut-off score = 38 ng/mL
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Screening test evaluationsensitivity
Among those with disease, what proportion does the screening test detect?
Interpretation: With a cut-off of 38 ng/mL, we have a test with 100% sensitivity.
Among those with prostate cancer, the test captures all cases. There are no false
negatives.
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Screening test evaluationspecificity
Among those without disease, what proportion does the screening test correctly
identify as disease free?
Interpretation: With a cut-off of 38 ng/mL, screening test classifies 61.2% of men
without prostate cancer as not having prostate cancer, remaining 38.8% are false
positive cases.
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Screening test evaluationsensitivity and specificity tradeoffs
Test cut-off is very sensitive: All those who have the disease will be captured by the testTest cut-off is very specific: Individuals who do not have the disease are will not screen positiveHigh sensitivity/low specificity tests are common in practice; i.e., we will not miss many individuals with disease but we also will screen positive those who do not have disease
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Screening test evaluationsensitivity and specificity, example
Primary care physicians query patients about whether they
engaged in at least one episode of heavy drinking in the past year
as a screening tool for identifying individuals with an alcohol
disorder
Almost all individuals with an alcohol disorder will have engaged in
at least one episode of heavy drinking in the past year, but many
individuals without an alcohol disorder may have engaged in one
or more heavy drinking episodes as well.
The test is sensitive, but not specific
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Screening test evaluationPPV, NPV, and prevalence
How well does our screening test predict who is diseased and who is not?
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Screening test evaluationpositive predictive value
Among those who screen positive, what proportion actually has the disease?
Interpretation: With a cut-off of 38 ng/mL, one fifth of the men who screen positive
on test have prostate cancer, leaving about 80% of men screening positive falsely.
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Screening test evaluationnegative predictive value
Among those who screen negative, what proportion actually do not have the
disease?
Interpretation: With a cut-off of 38 ng/mL, the test has perfect negative predictive
value. Among those who are negative on the screening test, we can be perfectly
confident that none of those individuals actually have the disease.
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Screening test evaluation
Assess sensitivity and specificity to understand the proportion
of diseased and non-diseased individuals correctly categorized as
diseased and non-diseased
Assess PPV and NPV to understand the proportion of positively
screened and negatively screened individuals that have disease
or are disease-free
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Screening test evaluationcut-offs and tradeoffs, example
Hypothetical screening test for prostate cancer set a cut-off of 38 ng/mL Perfect sensitivity and negative predictive value Low specificity and positive predictive value
Change cut-off for positivity to 45 ng/mL Individuals are positive on screening test if level of
antigen is 45 ng/mL or above
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Screening test evaluationcut-offs and tradeoffs, example
Compared with original cut-off of ≥ 38 ng/mL
Sensitivity decreased and specificity increased
Positive predictive value increased
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Screening test evaluationcut-offs and tradeoffs
Original cut-off
Why did sensitivity decrease?
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Screening test evaluationcut-offs and tradeoffs
Original cut-off
Why did sensitivity decrease?
Some individuals who have prostate cancer will screen negative now - false negatives
As increase cut-off for positivity on a screening test, number of individuals with the disease who screen negative will increase - leading to lower sensitivity
New cut-off
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Screening test evaluationcut-offs and tradeoffs
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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Ramifications of false positives vs. false negatives
Low rate of false negatives preferred Infectious diseases critical to maintain low rate of false
negative When disease can be readily remediated if caught early but
devastating if notLow rate of false positivity preferred When subsequent diagnostic test is invasive and expensive
procedures Screening is done routinely on low burden diseases
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A note
Empirical guidelines for screening can be created to optimize screening cut-points; these are usually derived from receiver operating characteristic (ROC) curves
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Multiple-stage screening
Two-stage screening test1. Screen individuals using test with high sensitivity2. Follow-up with test with high specificity
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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Prevalence of screening health indicator, example
Antigen screening test Cut-off of 45 ng/mL Screen two samples for prostate cancerA. 1,500 men with prostate cancer family history; > 60
years oldB. 1,500 men with no prostate cancer family history; 40-60
years old
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Prostate cancer screening, sample A
Men with prostate cancer family history and > 60
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Prostate cancer screening, sample B
Men with no prostate cancer family history and 40 - 60
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Prostate cancer screening example
Sensitivity and specificity
Sample A and Sample B sensitivity = 90%
Sample A and Sample B specificity = 83%
PPV, positive predictive value
Sample A (family history, >60) PPV = 72.7%
Sample B (no family history, 40-60) PPV = 3.4%
NPV, negative predictive value
Sample A (family history, >60) NPV = 94.5%
Sample B (no family history, 40-60) NPV = 99.9%
PPV and NPV differ across samples. Why?
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Why does PPV change?
PPV is dependent on the prevalence of a health indicator in screened population
As prevalence probability that individual who screens positive will be true case
As prevalence probability of being true negative case
Sensitivity and specificity are not directly influenced by prevalence
Sensitivity and specificity look among those who have the health indicator versus those who do
not
PPV and NPV are dependent on prevalence, and PPV increases as the prevalence of disease
increases.
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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Screening test to screening program
Example 1: Detection based on screening compared with detection based on symptoms Example 2: Detection based on screening compared with effect of screening on mortality
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Example 1: Cancer duration in Farrlandia
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Example 1: Cancer duration in Farrlandia, screening at 10 years
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Example 1: Cancer duration in Farrlandia, screening at 10 years
Screening at single time point is estimating the prevalence of cancer at time pointCancer cases that are more likely to be detected have long duration and perhaps slow-growing tumorsProblems with this1. Slow-growing tumors may not eventually cause death or disability - difficult to
predict which tumors will become symptomatic and which will not2. Compare cancer-related mortality among screened sample to non-screened
sample Screened group may have fewer cancer-related deaths because may have
better cancer-related outcomes Because tumors that are detected more likely to be slow growing tumors
that did not influence morbidity and mortalityLength-time bias: Inability to estimate the causal impact of screening test on morbidity and mortality
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Example 2: Disease detection by screening vs. symptoms
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Example 2: Screening vs. symptom diagnosis
Person 1’s cancer detected through screening
Person 2’s cancer detected due to symptoms
Person 1 and person 2 have equal time from cancer onset to death
Time from cancer detection to death is longer in Person 1
Lead time: The time from detection from screening and detection through
symptoms afforded by screening test. This will always show a benefit in
the screened group - even if early detection did not really lengthen life
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Example 2: Disease detection by screening vs. symptoms
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Example 2: observation time
When time from start of observation to death is the same in both individuals - no association between screening and length of lifeWhen the time from start of observation to death shorter for the not screened compared with screened - evidence that early detection through screening has benefit on mortality
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1. What is screening?
2. When should we screen?
3. How do we evaluate a screening test?
4. How do we decide on a cut-off?
5. PPV, NPV, and prevalence
6. From screening test to screening program
7. Summary
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Summary
Screening for health indicators is integral part of improving population
health
Screening predicts who will develop a specific disease and detects
disease among those in early stages
Screening tests need to be studied for validity (sensitivity and
specificity)
We often have a trade-off between sensitivity and specificity
Predictive value of screening test is maximized in populations with high
prevalence of health indicator of interest
Value of screening program will depend on cost-effectiveness, minimal
invasiveness, availability of effective treatment
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