Evidence-Based Medicine (EBM):

Prognosis
Prof. dr. Mohammad Hakimi, SpOG(K), PhD.
Clinical Epidemiology & Biostatistics Unit
Gadjah Mada University Faculty of Medicine
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Clinical Issues and Questions in the
Practice of Medicine:
Prognosis:
What are the consequences of having the
disease?
What is this patients likely clinical course over
time?
For patients with osseointegrated implants,
what is the proportion of implants lost at 10
years?
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Questions about how patients illness will
affect them:
Is it dangerous?
Could I die of it?
Will there be pain?
How long will I be able
to continue my
present activities?
Will it ever go away
altogether?
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Prognosis:
A prediction of the future course of disease
following its onset
Review the ways in which the course of
disease can be described
Consider the biases that can affect these
descriptions and how these biases can be
controlled
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A difficult but indispensable task:
Predicting patients futures as closely as
possible:
To avoid expressing prognosis:

With vagueness when it is
unnecessary
With certainty when it is misleading
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Risk and Prognosis:
Risk factors:
Conditions that can be
identified in well
persons and, when
present, are
associated with an
increased risk of
acquiring disease
Prognostic factors:
Conditions that, when
present in persons
already known to have
disease, are
associated with an
outcome of the
disease
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Differences between risk and prognosis:
Risk:
Low probability events
The event:
Onset of disease

Risk factors are not
necessarily the same as
prognostic factors for a
given disease
Prognosis:
Relatively frequent
events
The event:
Death, complications,
disability, suffering,
etc.
Prognostic factors are
not necessarily the same
as risk factors for a given
disease
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RISK PROGNOSIS
Onset of Acute
Myocardial Infarction
Well Outcomes
Death
Reinfarction
Other
Risk Factors
Age
Male
Cigarette smoking
Hypertension
LDL / HDL
Inactivity
Prognostic (Poor) Factors
Age
Female
Cigarette smoking
Hypotension
Anterior infarction
Congestive heart failure
Ventricular arrhythmia
Differences between risk and prognostic factors for acute
myocardial infarction
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Natural history/Clinical course:
Natural history:
The evolution of disease without medical
intervention
Clinical course:
The evolution of disease that come under
medical care and is then treated in a
variety of ways that might affect the
subsequent course of events
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Sampling bias:
Reports of prognosis
based on experience in
academic medical
centers cannot be taken
as an accurate guide to
prognosis
Usually, reported cases
will have a worse-than-
average prognosis
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Describing outcomes of disease:
Should include the full range of
manifestations that would be considered
important to patients (5Ds):
1. Death
2. Disease
3. Disability
4. Discomfort
5. Dissatisfaction
6. (Destitution)
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Rates commonly used to describe prognosis:
Rate Definition*
5-year survival Percent of patients surviving 5 years from some
point in the course of their disease
Case fatality Percent of patients with a disease who die of it
Disease-specific
mortality
Number of people per 10,000 (or 100,000)
population dying of a specific disease
Response Percent of patients showing some evidence of
improvement following an intervention
Remission Percent of patients entering a phase in which
disease is no longer detectable
Recurrence Percent of patients who have return of disease
after a disease-free interval
*Time under observation is either stated or assumed to be sufficiently
long so that all events that will occur have been observed
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Components of rates:

Zero time
People at risk
Definition of events
Time to follow-up
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Zero Time:
A point in time when cohorts are started to
be observed
Should be specified clearly and be the
same
Inception cohort:
A group of people who are assembled near the
onset of disease
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Survival Analysis:
Presents information about average time-to-
event for any time in the course of disease
Censoring: patients are lost from the study at
any point in time
drop out
lost to follow-up
have outcome
Survival curves
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Prognosis shown as
survival curves
(dashed line indicates
median survival).

A: Good prognosis (or
too short a study!).
B: Poor prognosis
early, then slower
increase in mortality,
with median survival
of 3 months.
C: Good prognosis
early, then worsening,
with median survival
of 9 months.
D: Steady prognosis.
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Interpreting Survival Curves:
The vertical axis represents the probability of surviving for
members of a hypothetical cohort, not the percent
surviving for an actual cohort
Points on a survival curve are the best estimate, for a
given set of data, of the probability of survival for
members of a cohort
The shape of some survival curves, particularly those in
which most patients experience the event of interest,
gives the deceptive impression that patients die rapidly
early on, then reach a plateau at which the risk of dying is
considerably less
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Bias in Cohort Studies:
Assembly bias: groups of patients are assembled for
study that differ in ways other than the factors under study
Migration bias: patients in one cohort leave their original
cohort, either moving to one of the other cohorts under
study or dropping out of the study altogether
Measurement bias: patients in one of the cohorts stand a
better chance of having their outcome detected
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Case Presentation
We see a 45-year-old woman for a routine health visit
who has recently moved to the city and enrolled in our
practice. She is well and is on no medications. Her past
medical history is unremarkable. On cardiac examination,
auscultatory findings are suggestive of mitral valve
prolapse with mitral regurgitation. The remainder of the
examination, including heart rate, is unremarkable. On
further questioning, the patient states that shes been told
by a previous family physician that she has a heart
murmur. She asks us if she should be concerned about
this murmur.
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Mitral Valve Prolapse (MVP)
A disorder in which, during the contraction phase
of the heart, the mitral valve does not close
properly
When the valve does not close properly it allows
blood to backflow into the left atrium
Some symptoms can include palpitations, chest
pain, difficulty breathing after exertion, fatigue,
cough, and shortness of breath while lying down
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Practice of EBM
Step 1: Converting the need for information (about
prevention, diagnosis, prognosis, therapy, causation, etc.)
into an answerable question
Step 2: Tracking down the best evidence with which to
answer that question
Step 3: Critically appraise that evidence for the validity
(closeness to the truth), impact (size of the effect), and
applicability (usefulness in our clinical practice)
Step 4: Integrating the critical appraisal with our clinical
expertise and with our patients unique biology, values,
and circumstances
Step 5: Evaluating our effectiveness and efficiency in
executing steps 1-4 and seeking ways to improve them
both for next time
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Practice of EBM
Step 1: Converting the need for information (about
prevention, diagnosis, prognosis, therapy, causation, etc.)
into an answerable question
Step 2: Tracking down the best evidence with which to
answer that question
Step 3: Critically appraise that evidence for the validity
(closeness to the truth), impact (size of the effect), and
applicability (usefulness in our clinical practice)
Step 4: Integrating the critical appraisal with our clinical
expertise and with our patients unique biology, values,
and circumstances
Step 5: Evaluating our effectiveness and efficiency in
executing steps 1-4 and seeking ways to improve them
both for next time
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Clinical question about prognosis
Patient or
Problem
Intervention Comparison Outcomes
A 45-
year-old
woman
Mitral valve
prolapse with
mitral
regurgitation
No mitral
prolapse and
regurgitation
Cardio-
vascular
morbidity
and
mortality
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Clinical question about
prognosis
In a 45-year-old woman what is the risk
following mitral prolapse with mitral
regurgitation compared to without mitral
prolapse with mitral regurgitation of
subsequent cardiovascular morbidity and
mortality?
In a 45-year-old woman with asymptomatic
mitral valve prolapse, what is the risk of a
cardiac event or death?
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Practice of EBM
Step 1: Converting the need for information (about
prevention, diagnosis, prognosis, therapy, causation, etc.)
into an answerable question
Step 2: Tracking down the best evidence with which to
answer that question
Step 3: Critically appraise that evidence for the validity
(closeness to the truth), impact (size of the effect), and
applicability (usefulness in our clinical practice)
Step 4: Integrating the critical appraisal with our clinical
expertise and with our patients unique biology, values,
and circumstances
Step 5: Evaluating our effectiveness and efficiency in
executing steps 1-4 and seeking ways to improve them
both for next time
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Searching the Evidence
Using the Clinical Queries function of PubMed
(and clicking on the filters prognosis and
specificity), we were able to identify an article
that might help us to answer this question:
Avierinos JF, Gersh BJ, Melton J, et al.
Natural history of asymptomatic mitral valve
prolapse in the community. Circulation 2002;
106: 135561.
Full text
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Practice of EBM
Step 1: Converting the need for information (about
prevention, diagnosis, prognosis, therapy, causation, etc.)
into an answerable question
Step 2: Tracking down the best evidence with which to
answer that question
Step 3: Critically appraise that evidence for the validity
(closeness to the truth), impact (size of the effect), and
applicability (usefulness in our clinical practice)
Step 4: Integrating the critical appraisal with our clinical
expertise and with our patients unique biology, values,
and circumstances
Step 5: Evaluating our effectiveness and efficiency in
executing steps 1-4 and seeking ways to improve them
both for next time
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Clinical
domain
Question Epidemiological
study type
Diagnosis How accurate are tests
used to diagnose disease?
Cross-sectional
study
Prognosis What are the
consequences of having a
disease?
Cohort
(longitudinal)
study
Therapy How does treatment
change the course of
disease?
RCT (or
systematic review
of RCTs)
Harm
(Etiology/
causation)
What conditions lead to
disease?
Cohort or case-
control study
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Is this evidence about prognosis valid?
1. Was a defined, representative sample of
patients assembled at a common point in
the course of their disease?
Information about the study type and
sampling method is usually found in the
abstract and methods sections of the article
The study that we found is an inception
cohort including patients with asymptomatic
mitral valve prolapse
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Is this evidence about prognosis valid?
2. Was follow-up of study patients
sufficiently long and complete?
In the study that we found, follow-up was
97% at a median of 5.4 years, so no threat to
validity here!
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Is this evidence about prognosis valid?
3. Were objective outcome criteria applied in a
blind fashion?
In the mitral valve prolapse study that we found, the
outcomes included total mortality and cause of death
Cause of death was ascertained by hospital notes,
death reports, death certificates, and autopsy
records, or by contacting the patients physicians
It is not clear if the outcomes assessors were blinded
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Is this evidence about prognosis valid?
4. If subgroups with different prognoses are identified:
Was there adjustment for important prognostic factors?
Was there validation in an independent group of test-
set patients?
In our study, after adjusting for age, sex, and comorbid
conditions, moderate-to-severe mitral regurgitation and ejection
fraction <50% were found to be independent predictors of
cardiovascular mortality
The authors also identified several prognostic factors that
independently predicted cardiovascular morbidity and mortality
The significance of these prognostic factors was not confirmed
in a validation set
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Is this valid evidence about prognosis
important?
1. How likely are the outcomes over time?
2. How precise are the prognostic estimates?
From our study, we found that, at a median follow-up
of 5.4 years, mortality was 11.5%
Moderate-to-severe mitral regurgitation (hazard ratio
1.8, 95% CI 1.03 to 3.0) and ejection fraction <50%
(hazard ratio 2.3, 95% CI 1.05 to 4.4) were
independent predictors of cardiovascular mortality
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Can we apply this valid, important
evidence about prognosis to our patient?
1. Is our patient so different from those in
the study that its results cannot apply?
2. Will this evidence make a clinically
important impact on our conclusions
about what to offer or tell our patient?
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Practice of EBM
Step 1: Converting the need for information (about
prevention, diagnosis, prognosis, therapy, causation, etc.)
into an answerable question
Step 2: Tracking down the best evidence with which to
answer that question
Step 3: Critically appraise that evidence for the validity
(closeness to the truth), impact (size of the effect), and
applicability (usefulness in our clinical practice)
Step 4: Integrating the critical appraisal with our clinical
expertise and with our patients unique biology, values,
and circumstances
Step 5: Evaluating our effectiveness and efficiency in
executing steps 1-4 and seeking ways to improve them
both for next time
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Resolution of the Case
Returning to our patient, transthoracic
echocardiography revealed mild mitral regurgitation
and an ejection fraction of >65%
Given her age (<50 years) and the absence of the
other prognostic factors identified in the study that we
found, we can reassure our patient that she is
considered low risk for cardiovascular morbidity and
mortality, and that her outcome (with respect to mitral
valve prolapse) will be similar to that of the general
population
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