EPIDEMIOLOGY FINAL EXAM REVIEW, FALL 2009 ORIGINALLY COMPILED BY ADAM WOLFE, AMENDED BY JOHN SELBY

LOOK OVER ALL PREVIOUS REVIEW SHEETS WHEN STUDYING FOR THE FINAL EXAM!

Topic 1. Survival Analysis.

1. Retrospectively using death certificates (nave survival analysis) to identify causes of mortality is
actually a type of selection bias. For survival data the most appropriate method is to follow a
predefined cohort prospectively and to measure the time to death or some other clinically
relevant endpoint.

2. How to censor data. After a time interval in the study, anyone who has died or withdrawn from the
study will not be considered at future timepoints.

3. Kaplan-Meier survival curves. You might have to draw a curve on the exam, and you will
certainly be asked questions about the rules governing this type of survival analysis.
Rules: Always note withdrawals from the study. Dont change the graph until there is a death,
then calculate a new survival percentage at that time. At any point along the curve, the
cumulative probability of survival to this timepoint is indicated on the Y-axis.

4. Lets consider an example. Follow along on the accompanying Survival Analysis Example
posted on the class website under TA Handouts.
50 people, who were recently diagnosed with Disease A and had surgical treatment, are
followed for 60 days. On day 20, 4 patients die and 6 have moved out of state and are lost to
follow up. Look at slide #1. The curve is drawn at the 100% line (no deaths) until day 20. Now
we need to drop the curve, because some deaths have occurred. Also, during this time period
6 patients need to be censored. The probability of dying in the first interval equals the number
of deaths in the interval divided by number surviving at the previous timepoint minus the
number of withdrawals during the interval. In this example the probability of dying in the first
20 days is computed as: 4 / (50-6) = 4/44 = 0.09, or 9%. Therefore, the fraction of original
study participants surviving the first 20 days is 91%.
On day 35, 5 more patients die and 4 withdrew from the study. Thus, for those patients who
survived the first 20 days, the probability of dying between day 21 and day 35 can be
computed as 5 / (40-4) = 5/36 = 13.9%. In other words, in this second interval, there was
86.1% survival, given that someone survived the first interval. So for the total population curve,
we multiply the two interval survival fractions to find the fraction of original study participants
who survived the first 35 days: 0.91 x 0.861 = 0.783, or 78.3% (see slide #2).
By day 50, another patient has withdrawn and 6 die on that day. Thus, for those patients who
survived the first 35 days, the probability of dying between day 36 and day 50 can be
computed as 6 / (31-1) = 6/30 = 20%. So for the total population curve, we multiply the three
interval survival fractions to find the fraction of original study participants who survived the first
50 days: 0.91 x 0.861 x 0.8 = 62.7% (see slide #3).
At day 60, the end of our study, there are 24 patients left alive. Looking at our total
population curve, we can see that the probability of survival for Disease A after surgical
treatment at 60 days is approximately 62.7% (see slide #4).

5. Survival curves become less accurate as you move to the right (increasing time) because the
number of people being followed is decreasing.

6. If you want to calculate interval-specific survival probability, simply divide the height of the curve at
the desired interval by the height at the specified interval of reference. In the example above, the
probability of surviving for 60 days given that the person already survived to day 20 is
0.627 / 0.91 = 0.688, or 68.8%.

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EPIDEMIOLOGY FINAL EXAM REVIEW, FALL 2009 ORIGINALLY COMPILED BY ADAM WOLFE, AMENDED BY JOHN SELBY

Topic 2. Interpreting Medical Tests.

This lecture has some very high yield information for your Step I exam.
Be sure you understand the mathematical and semantic definitions of the bolded terms below.
1. Remember our table of test results versus disease? You need to be able to calculate the following
parameters from a 2x2 table:
False positive rate = b/(b+d)
False negative rate = c/(a+c)
Sensitivity = a/(a+c); the probability of having a positive test result if you have the disease.
Specificity = d/(b+d); the probability of having a negative test result if you do not have the
disease.
Positive predictive value (also called post-test probability of a positive test) is not the same
as sensitivity! It takes the prevalence of the disease into account. It answers the question, how
likely is someone from the population at large to have the disease, given a positive test result?
Mathematically, it is calculated as true positives divided by all positive tests.
Negative predictive value is not the same as specificity! How likely is someone from the
population at large not to have the disease, given a negative test? Mathematically, it is
calculated as true negatives divided by all negative tests.

Reality or Truth Reality or Truth Totals

Disease (+) Disease (-)
Test (+) a b a+b
Correct result! False positive!
Test (-) c d c+d
False negative! Correct result!
Totals a+c b+d a+b+c+d

2. It is unlikely that a single test can have 100% sensitivity and specificity. If it does, its probably not
a great test. Look at Dr. Gayeds slides from this lecture to see what happens when you select
different sensitivity and specificity values for a test on a graph of population values.
Receiver-Operating Characteristic (ROC) curve plots the change in sensitivity vs.
false-positive rate (1-specificity) for a typical test. Note that as we increase the sensitivity of
the test, the specificity decreases. Picking the best combination of sensitivity and specificity
is often challenging, and depends on how many false positives/negatives you are willing to
tolerate. A test is considered better if the area under the ROC curve is greater.
Now consider a disease that is not very prevalent. How do we interpret false positives and
negatives when testing for it? This is why we have predictive values.

3. Predictive values again. Just like case-control studies dont tell us anything about population
statistics, a case-control table cannot be used on its own to establish positive and negative
predictive values. We need prevalence (also called pre-test probability) of the disease and must
adjust the case-control table to reflect a proportional population. Consider this table from lecture:
Reality or Truth Reality or Truth Totals
Disease (+) Disease (-)
Test (+) 95 8 103
Test (-) 5 92 97
Totals 100 100 200
Sensitivity = 95%, specificity = 92%. If you were given this case-control table and asked to
calculate PPV and NPV, you would not have enough information to do so! Do not be tempted
to calculate it as 95/103 (92%)! We do not know prevalence yet.
Now lets say the prevalence of the disease is 10% in our population. We could adjust this
table, taking into account the sensitivity and specificity values above, to reflect a hypothetical
population of 1000 people:

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EPIDEMIOLOGY FINAL EXAM REVIEW, FALL 2009 ORIGINALLY COMPILED BY ADAM WOLFE, AMENDED BY JOHN SELBY

Reality or Truth Reality or Truth Totals

Disease (+) Disease (-)
Test (+) 95 72 167
Test (-) 5 828 833
Totals 100 900 1000
If you dont understand what was done here, re-calculate the sensitivity and specificity values.
You will see that they are still 95% and 92%. All we did was set up a population with 10%
disease prevalence (100/1000 disease +, 900/1000 disease -).
PPV = true positives/all positive tests = 95/167 = 57%.
NPV = true negatives/all negative tests = 828/833 = 99%.

4. Likelihood ratios. LR+ is the ratio of probabilities of a true positive to false positive test result, or
sensitivity / (1-specificity). LR- is the ratio of probabilities of a false negative to true negative test
result, or (1-sensitivity) / specificity. Note that both types of likelihood ratio are predicting the
likelihood of having the disease.
Look back at the table above. The LR+ would be sensitivity/(1-specificity) = 0.95/(1-0.92) =
0.95/0.08 = 11.9, so if I have a positive test I am roughly 12x more likely to have the disease
than to not have the disease.
LR- would be (1-sensitivity)/specificity = 0.05/0.92 = 0.054, so if I have a negative test I am
almost 20x less likely to have the disease.

5. Dr. Gayeds mnemonics.

SpIN: A test with a high specificity can be used to rule-IN a disease, because positive results
are more likely to be true positives than false.
SnOUT: A test with a high sensitivity can be used to rule-OUT disease, because negative
results are more likely to be true negatives than false.

6. Combination tests
Serial testing: perform multiple tests in a sequence as a cost-saving measure. If any test is
negative, stop testing. All must be positive to diagnose the patient. This method increases
the specificity above all of the individual tests, but lowers sensitivity below all of the
individual tests. 1-Sp (combination) = (1-Sp) x (1-Sp) x... for each individual test.
Sn (combination) = Sn x Sn x... for each individual test.
Parallel testing. Perform multiple tests simultaneously. If any one is positive, diagnosis is
made. Increases sensitivity above all of the individual tests, but lowers specificity below all of
the individual tests. 1-Sn (combination) = (1-Sn) x (1-Sn) x... for each individual test. Sp
(combination) = Sp x Sp x... for each individual test. Used to rule out serious but treatable
conditions, such as myocardial infarction.

Topic 3. Screening.
1. When do we screen for a disease? We should screen for a disease when the disease is common,
serious, treatable, slow to develop symptoms, and treatable in the asymptomatic condition, i.e.,
superior outcomes if treated when asymptomatic versus treatment when symptomatic. The test
should have high predictive values, be inexpensive, and something the patient and physician are
willing to perform. Ideally, a high sensitivity would be great, but its more important to have a high
specificity if the disease is not too common (less chance of false positives).

2. More biases:
Lead-Time Bias. We diagnose a disease based on when symptoms appear, and measure life
expectancy. Now we diagnose based on a screening test (pre-symptoms), and measure life
expectancy. Since our screening test found the disease earlier in the disease process, the
screened patients appear to live longer, simply because of the early diagnosis! This makes us
think that the screening prolonged their lives, even if the treatment had no effect.

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EPIDEMIOLOGY FINAL EXAM REVIEW, FALL 2009 ORIGINALLY COMPILED BY ADAM WOLFE, AMENDED BY JOHN SELBY

Length-Time Bias. Similar to above, this bias makes us think that screening prolongs life,
even if the treatment is ineffective. In this case, our screening test detects patients who have
slow-progressing variants of the disease. Fast-progressing patients become symptomatic
quickly, and also die quicker, but if we just lump everyone together it looks like the screening
prolonged survival.
Compliance (Volunteer) Bias. Same as from a previous lecture. People who volunteer for
medical testing (including screening) tend to take better care of themselves overall and are
more likely to comply with treatment. As a screening population, they appear to do better than
the general population even if the early treatment is not very effective.

Topic 4. Case study: Screening for HIV. This case study reviews all of the issues described above
under Screening.

Topic 5. Decision Analysis. I strongly recommend that you look back over Dr. Gayeds lecture slides
and attempt to draw out the decision tree for the decision analysis assignment he provided in class.
While you may not be asked to draw a decision analysis tree for your exam, you will probably be
asked to analyze one and should understand what all of the symbols and numbers represent in a
completed tree.
1. You are given a number of interventions for a particular problem, and the probabilities of certain
outcomes from each intervention. These outcomes can be things such as cure, improvement,
worsening, death, etc. If an intervention is actually a test of some kind, the probabilities of each
outcome (based on predictive values) are provided.

2. Start your analysis by drawing a tree with each intervention/test the subject might choose.
The branches of the tree, then, represent every possible combination of interventions and
outcomes. Use boxes to indicate places where the subject can make a decision, circles to indicate
events determined by chance occurrences, and ovals to indicate endpoints.

3. At each branch point, enter the probabilities for each new branch.

4. At each endpoint, assign utilities. These can be concrete values, such as life expectancies, or
arbitrary values, such as the patients perceived quality of life.

5. Fold back the tree. This means that you start at the endpoints, and multiply each endpoint utility
by the probability on that branch (going back to the last chance or decision point). Now add
together all of these products (weighted utilities) for the node. This sum is the overall utility of the
node (either a decision or chance node). Now repeat this process at each node, working to the
base of the tree. You will ultimately have a weighted utility for the very first decision point, which
represents a suggestion of which choice represents the most likely good outcome for the patient.

6. Sensitivity analysis. What if our arbitrary utilities biased our ultimate decision? You can go back to
your utilities, and adjust the numbers. For example, if the patient originally gave a utility of 1.0 for
the outcome improvement and utility 0.5 for the outcome no change, try adjusting the
no change utility to 0.75, fold back the tree again, and see if the decision recommendation
changes. The larger of a change in utilities required to affect a change in the decision
recommendation, the more robust the tree was.
Note: sensitivity analysis in this context has nothing to do with sensitivity of diagnostic tests
discussed in another lecture!

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EPIDEMIOLOGY FINAL EXAM REVIEW, FALL 2009 ORIGINALLY COMPILED BY ADAM WOLFE, AMENDED BY JOHN SELBY

Topic 6. Making sense of multiple studies.

1. The more tests you run indiscriminately on patients, the more likely there will be some abnormal
finding. Does this mean that everyone has something wrong with them? Probably not. Remember
from the statistics lecture that most lab tests determine a normal result based on an interval that
includes the middle 95% of the general population. That means that on any one test there is a 5%
chance that a normal person has a value outside of the normal range for the test. If you
randomly test someone for 20 serum markers all at once, it is very likely that you will find an
abnormality, even though nothing is wrong.

2. For the reason just explained, it is important to have an indication to order a test on a patient.
The indication represents an increased suspicion or pretest probability on the clinicians part,
increasing the likelihood ratio that the test will have a correct and useful result.

3. During a clinical trial, each time you check patient status mid-trial you actually raise your value
(reducing the statistical significance of your findings). Why? Because each time you look in on
the trial results, its like performing another test and random variation from test to test increases
your probability of finding a result based purely on chance. This phenomenon is called
consumption. Obrien-Fleming rules are used in clinical trials to determine threshold p values for
deciding whether or not to terminate the trial depending on the number of times you look in on
the data.

4. Causality between an exposure and an outcome:

Strength of association: a higher relative risk makes the causality easier to detect/prove.
Consistency: multiple studies with different populations and test methods that detect the same
association between exposure and outcome is strong evidence for causality.
Temporality: exposure must precede outcome.
Dose-response: more exposure increases likelihood or severity of the outcome.
Reversibility: discontinuing exposure reduces risk of the outcome.
Biologic plausibility: a scientific explanation how the exposure causes the outcome. In many
instances, biological plausibility follows the establishment of causality. Think back to the
studies that linked cigarette smoking to lung cancer. Even today, the pathophysiological
mechanisms underlying the relationship are not completely known.
Specificity: one cause leads to one effect.
Analogy: this exposure-disease relationship resembles a different one that is well-established.

5. What are the types of research that establish a cause-effect relationship? From worst to best:
case report, case series, case-control, cohort study, clinical trial.

6. Meta-Analysis. A meta-analysis pools the results and observations from multiple studies in the
literature to try and improve the statistics of the smaller studies. Bigger N = better combined
power. However, any biases and confounding factors present in those studies are still present.
All the meta-analysis does is to help us form a hypothesis for the design of a larger clinical study,
with better power and narrower confidence intervals.
Publication Bias. The meta-analysis will only include studies that got published. However,
negative results are much less frequently published than positive ones. So trials that failed
might not make it into the meta-analysis. We can check for this and other biases by drawing a
funnel plot of all of the constituent studies of the meta-analysis. The funnel plot features a
vertical axis relating to the power of the studies and a horizontal axis showing the observed
effect in each trial (effect might be odds ratio, etc.). A meta-analysis containing few biases
should show a funneling of studies as their powers drop. In other words, the low-power studies
will scatter about the summary odds ratio symmetrically. If the plot is asymmetric, and
low-power studies all fall to one side or the other of the summary odds ratio, then we suspect

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biases, such as publication bias, may have weighted the types of studies that appeared in the
meta-analysis and therefore we should not trust its conclusions.

7. Make sure when you read an article to examine exclusion criteria. How many patients were
originally enrolled? How many were excluded based on predetermined criteria? How many were
randomized into each arm of the trial? How many dropped out during the trial?

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