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Lec 1-2 ORIENTATION INTRO TO CLINICAL QUESTION

ASK: Convert the need for information into an answerable question.
ACQUIRE: Track down the best evidence with which to answer that question.
APPRAISE: Critically appraise the evidence for its validity, impact, and applicability.
APPLY: Integrate the evidence with clinical expertise and our patients characteristics
/ values
ASSESS: Monitor how the intervention works in my patient or patient population.
PICO
Directly relevant to the care of the patient and our knowledge deficit.
Contains the following 4 elements:
PATIENT or PROBLEM being addressed
INTERVENTION or Exposure being considered
COMPARISON intervention or exposure, when relevant
OUTCOME of interest (final outcomes best)
Lec 3-4 EPIDEMIOLOGY: STUDY DESIGN SUMMARY
Objectives
Determine what study design was used in a particular paper
Make judgments about relative strengths/weaknesses of various study designs
Identify confounders in a particular study
Identify sources of bias in a particular study
Case Report or Case Series
Advantages
Useful when the disease is uncommon
First to provide clues to identify a new disease, adverse effect, new
surgical technique
Disadvantages
Usually small sample size
Cross-Sectional Studies
Advantages
Useful for assessing the prevalence of a disease or outcome
Good for examining exposures that do not change over time
Disadvantages
Are mainly descriptive
Cannot determine incidence
Cannot assess causality
Case Control Studies
Advantages
Quick - can overcome temporal delays (long time for outcome or disease to
develop)
Require reasonably small numbers

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Reasonably economical
Sensible for study of rare diseases
No loss to follow up
Can test current hypotheses
Consistency of measurement easily maintained
Good for Harm study, when not ethical or feasible to do an RCT
Disadvantages
Uncertain if exposure preceded disease
Potential for recall bias (sick people may be more [or less] likely to recall
exposure)
Selection bias (recruitment influenced by exposure)
May be unable to estimate disease incidence
Unmeasured confounding variables especially when an exposure varies over
time
Cohort Study
Advantages
Can collect exposure information as exposure happens
Can collect multiple exposures
Exposure information should be relatively reliable
Can collect information as outcome happens
Good for Harm study, when not ethical or feasible to do an RCT
Disadvantages
Duration of study: may take decades to complete
Loss to follow-ups potentially invalidate the study
Cost: very expensive
Potential for surveillance bias
7 Basic Designs (Quantitative)

No Comparison Group + Observational

Case Report
We had this guy.

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GENERALIZABILITY limited info

Case Series
We found these folks - assemble a number of patients or cases of a
particular phenomenon, and proceed to describe the common aspects of
those patients or cases
DESCRIPTIVE STATISTICS
o Can only be suggested as representing something real in the world
outside the study, because no population of patients within the study to
compare the case patients to
Comparison Group + Observational
Cross-Sectional Study
Key feature: One point in time
Assemble 2 or more groups and make comparisons
Example
Researchers assembled a group of non-smokers (group A on the diagram) and
a group of smokers (group B on the diagram), and measured the blood
pressures of everyone at a single point in time.
The researchers then plotted blood pressure on the x axis and, for each given
blood pressure value, on the y axis how many patients had that blood
pressure. The researchers then compared the mean values of blood pressure
for the two groups.
So, the question remains, does smoking CAUSE high blood pressure. With the
cross-sectional design, one cannot say for sure. All one can demonstrate here
is that smoking might be ASSOCIATED with blood pressure, but one cannot
say whether it CAUSES high blood pressure
CROSS SECTIONAL DESIGNS CANNOT DETERMINE CAUSATION because there is no
distinction between which factors come before others. In other words, cross
sectional studies do not have a TIMELINE.
Case-Control Study
Start with the disease Look BACKWARD in time for the risk factor
On our spectrum of study designs, the case control study is the FIRST one to
include TIME as a part of the design of the study
If the cases have a higher percentage of the risk factor, then this is evidence
that the thing we are studying IS an actual risk factor for the disease (causal
connection)
Bias- SYSTEMATIC difference in either forming or measuring the studys comparison
groups.
Case Control - subject to bias in measurement
Study participants remembering the risk factor (recall bias)
Investigators asking about the risk factor (observation bias) avoid by
blinding

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Selecting study participants (selection bias)

Cohort Study
Start with the risk factor Look FORWARD (Wait over) time and see who
gets the disease
Note that in a cohort, we dont usually find a control for every case
because start with the risk factor, rather than the disease
In a cohort, we try to enroll as representative a sample from the population we
are interested in as possible, then we separate out those with the risk factor
from those without the risk factor, and follow both groups to see what
percentage of the disease shows up in each group
Confounding - An alternate explanation for the study findings
OUTSIDE OF THE CAUSAL CHAIN between the supposed risk factor and
disease, but can provide an ALTERNATE PATHWAY from the supposed risk
factor to the disease.
To be a confounder, a particular factor needs to be INDEPENDENTLY
associated with BOTH the risk factor and the disease outcome
Comparison Group + Experimental
Randomized Trials
RANDOMLY select who goes into the study groups
Intervene on one of the groups
Measure the outcomes in the groups
Randomization allocates ALL confounders (both known and unknown)
EQUALLY among the study groups
Different from Cohort because of randomization
Randomization is so powerful because, if there are big enough numbers of
people in the study, all of the confounders will be distributed EQUALLY
between the two study groups and thus neutralized
o Reduce effects of confounders.
Causation
Exposure precedes outcome (only in studies with a timeline can show
causation)
Dose - response gradient (amount of the exposure is related to the amount of
the outcome)
Association consistent across studies
Face validity - association makes sense
Strength of association (large effect size)
Systematic Reviews
Combine evidence from multiple studies
Can incorporate large volumes of evidence about a topic
Are only as valid as the original studies that generated the evidence

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A System for Reading a Paper
What kind of study design is it? (abstract)
Is the study susceptible to bias? (methods section)
Recruitment (selection bias)
Measurement (recall and observation bias)
Are there potential confounders?

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Lec 3-4 -BASIC BIOSTATISTICS
Statistics
Constructs meanings by looking for mathematical patterns in the real world
Try predict the occurrence of future events and make decisions based on
those predictions
Statistics underlie most of the medical decisions we make
Apply to populations (not individuals)
Uses of Statistics
Statistics for Description
o Mean, median
Statistics for Certainty
o P value, confidence intervals
Statistics for Association
o Relative Risk, Absolute and Relative Risk Reduction
Statistics for Meaning
o NNT, NNH
Statistics for DESCRIPTION (properties and generalization)
Mean - simply the average
can apply additional mathematical statistics to decide how certain you are
that the data reflects whats out in the real world
Median - middle value when placed in order from lowest to highest
ODD number of observations - clear cut middle value.
EVEN number of observations, there would be two values in the middle the
median would then be the average of these two values.
Example
100, 100, 102, 104, 104
o Mean: (100+100+102+104+104)/5 = 102
o Median = 102
100, 100, 102, 104, 200
Mean: (100+100+102+104+200)/5 = 121
Median = 102
Statistics for CERTAINTY (how well sample populations reflect the real
world)
P values (P < 0.05)
Means: the chances of getting a result like this, if there were REALLY no
difference between the groups, is 5 percent (0.05) or less
THEREFORE: we conclude that there must actually be a difference between
the groups, because the probability of getting a result like this is so low.
gain some sense of certainty about whether difference was a fluke or not
whether that result popped up by chance.
0.05 is just a common convention for STATISTICAL SIGNIFICANCE

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HOWEVER, remembering that any study is just an approximation of the real world,
what might the REAL difference be out there in the world? Could it be even higher?
We use the CONFIDENCE INTERVAL to look at this.
First though, we need to look at how we compare groups. EFFECT SIZE is the size
of the difference between the two groups.
Effect sizes can be measured two ways
o One is to measure the difference between the two groups by simply
subtracting the means
o Another way is to take the mean of group a, and express it as a fraction
of the mean of group b.
You will see effect sizes reported both ways in the medical literature. Neither
way is better, but the particular way results are reported can have important
psychological effects on us readers as we will talk about when we look at
statistics for association.

95% confidence interval (CI) - be 95% certain that the REAL effect size out there
in the world is somewhere between # to #
the value of the confidence interval over just a p-value
o gives you the upper and lower bounds for an effect size
o a measure of the amount of certainty you can apply to these bounds.
95% is the general convention that is used for confidence intervals, but may
make it more stringent by increasing the number (99% confidence interval)

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If that interval includes the number 0 (if the effect size were 0 when measured
as a subtraction) that would mean that there is 0 difference between the two
groups, or NO EFFECT ie the groups are the same.
When the effect size is measured as a SUBTRACTION and the 95% confidence
interval includes the number 0, there is NOT a statistical difference between
the two groups.
Now look at the p-values.
o If the 95% CI does NOT include the number 0, the p-value is less than
0.05.
o When the CI includes the number 0 the p value is greater than 0.05
When dealing with fractions of the effect size, the number 1 means the mean blood
pressures of group a and group b were the same.
When using FRACTIONS, if the confidence interval includes the number 1,
then the groups are NOT statistically different.
So remember, with SUBTACTIONS, the magic number is 0, with FRACTIONS,
the magic number is 1.
If you have both (for example, a SUBTRACTION in the NUMERATOR of a
fraction) then the SUBTRACTION takes precedence, and you look for the
confidence interval to include the number 0.
This is an issue with relative risk reductions, which we will talk about next.
Statistics for Association (understand the magnitude of differences)
Absolute Risk Reduction control event MINUS study rate event
Relative Risk - the study group event rate OVER the control group event rate
Relative Risk Reduction - difference between the control and study event rates,
divided by the control event rate.
Example
Group a: 100 kids in daycare
o 20 get ear infections
o Control group event rate (CER) = 0.20
Group b: 100 kids at home
o 10 get ear infections
o Study group event rate (SER) = 0.10
Absolute Risk Reduction (ARR) = (CER-SER) = 0.20-0.10 = 0.10
Relative risk (RR)= (SER/CER) = 0.10/0.20 = 0.50
Relative Risk Reduction (RRR)= (ARR/CER) = (0.20-0.10)/0.20 = 0.50
Note: the relative risk reduction will not always be the same as the relative
risk
Ask whether this difference is really CLINICALLY SIGNIFICANT or not.
Both ARR and RRR are right

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A study that shows a risk of 4% in the control group and 2% in the study group
will have a relative risk reduction of 50%, but an absolute risk reduction of
only 2%,
Must ask ourselves: will that 2% make a whole lot of clinical difference for the
patient?

Statistics for Meaning (put into clinical perspective/decide how important)

Number Needed to Treat and Number Needed to Harm - calculated exactly the same
way
NNT focuses on desired, or good, outcomes,
NNH focuses on undesired, or bad, outcomes.
Not reported much in literature (must memorize eqn)
The Number Needed to Treat (NNT = 1/ARR)
In our hypothetical study:
o ARR = 0.20-0.10 = 0.10
o NNT = 1/ARR = 1/ 0.10 = 10
You would need to treat 10 kids (by keeping them home for ONE YEAR) to
prevent ONE ear infection in the class
Why NNT?
A new drug comes out to reduce heart attack risk by reducing cholesterol
o The drug costs $150 per month
o In a new study 10/400 (CER = 0.025) untreated folks had heart attacks
in 1 year, whereas 5/400 (SER = 0.0125) folks on the drug had heart
attacks
The company touts the 50% reduction in heart attacks (RRR)
o ARR = 0.025 0.0125 = 0.0125
o NNT = 1/0.0125 = 80
You would need to treat 80 people for 1 year (at a cost of $150 x 12 months x
80 = $144,000) to prevent one heart attack
NNH
Now suppose this drugs bad side effect was chemically induced hepatitis.
In the same way you calculate a NNT, you could also calculate a NNH.
Suppose in this example the NNH was 40.
Now consider you would need to treat 80 people to prevent one heart attack,
but in doing so, 2 of those 80 people would get chemically induced hepatitis
another thing to consider in clinical decision making
Lec 6 DIAGNOSTIC TESTING
Diagnosis
Conclusion reached by identifying a medical condition
Purpose of diagnosis is to identify a health state that warrants intervention or
correction

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Critical appraisal of physical signs and symptoms from various procedures and
tests

4 possibilities with any diagnostic scenario reflecting potential outcomes of a test

and the presence or absence of disease.
Outcome A is a True Positive, which occurs when a test is positive and the
disease is actually present.
Outcome D reflects a True Negative, which occurs when a test is negative
and the disease is actually absent.
Outcome B reflects a False Positive because the test result was positive but
the disease was actually absent.
Finally, Outcome C is a False Negative, because the test result was
negative and the disease was actually present. The possibility of Outcomes B
and C reflects the real-world fallibility of all diagnostic tests.

Criterion (Gold) Standard

The validity of diagnosis is based on criteria strength for determining whether a
disease is present
Consensus method or set of criteria for defining the presence of disease
Gold standards are often elusive due to clinical and epidemiological limitations
Pitfalls in diagnostic Testing
Inadequate data for all four quadrants
o Lack of info on negative test results (no definite cut off score)

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o Lack of info on test results in non-diseased (incidental findings)
o Lack of objective standards for disease (subjectiveness)
Pretest Probability (probability of disease)
Prevalence
Total # of cases within a given population
Provides anchor for framing pre-test probabilities
Clinical context matters
dont send home sick ER patients ie false neg bad
dont give radiation to neg patients ie false pos bad)

DISEASE
TEST

+
-

Post-test

+
True Positive
a
False Negative
c

False Positive
b
True Negative
d

a+c

b+d

a+b
c+d
a+b+c+d

Sensitivity = a/ a+c
Specificity = d/ b+d
Prevalence = a+c/ a+b+c+d
Sensitivity (= a/a+c)
Proportion of True positives among all those with the disease
Positive In Disease
Used to rule-out conditions
o Low false negative
o Especially when there is significant penalty for missing a diagnosis
First line screening test - Helpful when a battery of assessments is needed
to establish a diagnosis
Specificity (= d/b+d)
True negatives among all those without disease
Negative in Health
Used to rule-in conditions
o Low false positive
Important when treatment carries significant risks or side effects
o Final or confirmatory tests

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Post test Probability
Sensitivity and Specificity best for deciding whether or not to test / choosing the
best test
Once a test is used Post-Test Probabilities
Discern whether or not someone has a condition given that a test
result is known
Determinants of Predictive Value
Prevalence = prior / pretest probability
Predictive values = post-test probabilities (calculated using specificity and
sensitivity when the prevalence of a condition is known.)
Positive PV =
Sensitivity x Prevalence
_
(sensitivity x prevalence) + (1-specificity) x (1-prevalence)

DISEASE
TEST

+
-

Post-test

+
True Positive
a
False Negative
c

False Positive
b
True Negative
d

a+c

b+d

a+b
c+d
a+b+c+d

Positive Predictive Value = a/ a+b

Negative Predictive Value = d/ c+d
Prevalence = a+c/ a+b+c+d
(+) Predictive Value: proportion of people with a positive test result who have a
disease divided by all those with positive test results
PPV = (a/a+b)
PPV = True positives tests among all positive tests
(-) Predictive Value: proportion of people with a negative test results who do not
have a disease divided by all those with negative test results
NPV= (d / c+d)
NPV = True negative tests among all negative tests
Prevalence
IMPACTS pre-test probabilities

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o If high prevalence then pre-test probability of that diagnosis is higher

than for a condition with a low prevalence (common things are
common)
IMPACTS the predictive values
o Higher prevalence translates to higher positive predictive value
Sensitivity and specificity NOT affected prevalence
Common pitfalls:
o Prevalence in the population
o Prevalence among selective demographic groups
o Specific clinical setting shapes pre-test probabilities
o Referral process increases prevalence (esp if unusual/rare)

Diagnostic Reasoning Drawbacks

Actual test results rarely dichotomous, diseases are continuous, lots of false
pos/neg
Two limitations of PPVs and NPVs (Post test limitations)
o Influenced by prevalence of disease
o Rely on having clear thresholds for positive and negative test results
Likelihood Ratios
Are calculated from empiric test rests
Are helpful because they dont rely on artificial cut-off scores
o Magnitude of the LR varies with incremental changes in test results
Limitation is that they are based off Odds Ratios
o Odds are intuitively difficult concepts
o LR Nomograms can translate pre-test probabilities directly into posttest probabilities without ORs
LR = L1/L2 = test result in disease / test result in no disease
o Likelihoods (L1 & L2) are both proportions (Compares two likelihoods)
o L1: How likely a given test result will occur in those with the disease
o L2: How likely the same test result occurs in those without the disease
Interpreting LRs: Three Zone
LR >1
o Numerator is greater
o Test result occurs more often in those with disease
o LR>1 means in post-test probability of disease
LR=5 means test result occurs 5x more often in those with
disease than in those without disease
LR <1
o Denominator is greater
o Test result occurs more often in those without disease
o LR<1 means in post-test probability of disease
LR=0.2 means test result occurs 5x less often in those with
disease than in those without (LR=1/5)

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Test result occurs 5x more often in those without disease than in

those with disease

LR=1
o Just as likely in those with and without disease
o No change from pretest to post test probability

Significance of Likelihood
Ratio
Large
Moderate
Small
Tiny
No Change

High Likelihood Ratios

Low Likelihood Ratios

>10
5-10
2-5
<2
1

<0.1
0.1-0.2
0.2-0.5
>0.5
1

Calculating LRs from Sensitivity and Specificity Measures

Positive Likelihood Ratio = True Positives /False Positives = (sensitivity)/(1specificity)
Negative Likelihood Ratio= False Negative /True Negative = (1-sensitivity)/
(specificity)
Post-Test Probability using LR
Post-test odds = pre-test odds * LR
Pre-test odds = pre-test probability / (1-pre-test probability)
Post-test probability = post test odds / (post test odds + 1)
Convert pre-test into post-test probability
Fagan Nomogram

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