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Prognosis - EBM - Bahan Kuliah Yg Dipakai - 1
Prognosis - EBM - Bahan Kuliah Yg Dipakai - 1
Darwin Amir
Staf Pengajar S2 Kebidanan
Fakultas Kedokteran Universitas Andalas
Objectives:
1. Review definitions.
2. Understand concept of natural history and inception
cohort studies.
3. Define commonly used measures of prognosis.
4. Understand origins of bias in follow-up studies.
5. Understand basic statistical methodology for survival
data.
6. Define characteristics of an ideal prognostic study.
7. Understand the rationale and development of clinical
decision/ prediction rules
2
“Prediction is very difficult, especially
about the future”
-Niels Bohr
3
I. Definitions
• Prognosis: the prediction of the future course of
events following the onset of disease.
• can include death, complications, remission/recurrence,
morbidity, disability and social or occupational function.
4
I. Definitions
• Natural history: the evolution of disease
without medical intervention.
5
Natural History Studies
6
Natural History Studies
7
Natural History of Disease
Preclinical Clinical
Disease Prognosis
onset Diagnosis
8
Identifying the Onset of Disease
Infectious diseases
• Exposure (bite, infection, etc.)
• Biological culture
• Presence of antibody responses, viral DNA and
RNA
9
Identifying the Onset of Disease
Cancer
• Initial damage from radiation or chemicals
• First cancer cell division
• Lost of cell replication
• Screening for pathologic changes during preclinical phase
• First evidence of signs and symptoms
• Medical diagnosis of disease
11
Expressing Prognosis
12
Expressing Prognosis: Case-Fatality Rate (CFR)
Case-fatality (rate) =
Number of people who die of a disease
Number of people who have the disease
Example
200 people with the disease
20 deaths from the disease
CFR = 20x100 = 10%
200
13
Expressing Prognosis: Five-Year Survival
• Five-year survivalis the proportion of patients who are
alive five years after diagosis
Preclinical Clinical
Disease
onset Prognosis = a live 5 years
Diagnosis
14
II. Bias in Follow-up Studies
• Examples:
• differences in starting point of disease (survival cohort)
• differences in stage or extent of disease, co-morbidities,
prior treatment, age, gender, or race.
15
Survival Cohorts
• Survival cohort (or available patient cohort) studies
can be very biased because:
• convenience sample of current patients are likely to be at
various stages in the course of their disease.
• individuals not accounted for have different experiences
from those included e.g., died soon after trt.
16
A. Selection Bias
• ii) Migration bias
• occurs when patients drop out of the study
– (lost-to-follow-up).
• usually subjects drop out because of a valid reason
– e.g., died, recovery, side effects or disinterest.
• these factors are often related to prognosis.
• asses extent of bias by using a best/worst case analysis.
• patients can also cross-over from one exposure group to
another
– if cross-over occurs at random = non-differential
misclassification of exposure
17
A. Selection Bias
• iii) Generalizability bias
• related to the selective referral of patients to
tertiary (academic) medical centers.
• highly selected patient pool have different clinical
spectrum of disease.
• influences generalizability (see Moltusky, 1978;
Melton, 1985).
18
II. Bias in Follow-Up Studies
• B. Measurement bias
• Measurement (or assessment) bias occurs
when one group has a higher (or lower) probability
of having their outcome measured or detected.
– likely for softer outcomes
• side effects, mild disabilities, subclinical disease or
• the specific cause of death.
19
B. Measurement bias
• Measurement bias can be minimized by:
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III. Commonly Used Measures of
Prognosis
• A. 5-year Survival Rate
21
Fig. Limitation of 5-year Survival Rates
(From Fletcher)
100
80
% Surviving
0
0 1 2 3 4 5
Years
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B. Case-fatality Rate (CFR)
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IV. Statistical Methods Used in
Prognosis Studies
• A. Analysis of Survival or Failure Time Data
• primary end point of prognosis studies is time until
event of interest occurs e.g., death or relapse.
• analysis of survival or failure time data, requires
specific techniques:
– Kaplan-Meier estimator
– Log-rank test
– Cox proportional hazards regression model.
24
Censoring:
• Defn: when the event of interest does not
occur in all individuals because:
• study was stopped before everyone in the study
had the event
• loss to follow-up
• death from other (competing) causes e.g., road
traffic accidents
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Censoring
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Survival function (S(t))
• Defn: the probability of survival to a given point in
time (t)
27
A Typical Survival Curve Showing the Survival
Function (S(t)) Plotted Against Time with a
Median Survival Time of 1.25 Years
0.8
0.6
S(t)
0.4
0.2
0
0 1 2 3 4 5
Years
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Hazard function (h(t))
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Kaplan-Meier Estimator
• a widely accepted method of estimating S(t).
• S(t) is expressed as the product of conditional
probabilities e.g.,
• S(3)= S(1) x S(2|1) x S(3|2)
• where:
– S(1)= probability of surviving year 1
– S(2|1)= conditional probability of surviving year 2,
given survival to year 1.
– S(3|2)= conditional probability of surviving year 3,
given survival to year 2.
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Kaplan-Meier Estimator
• estimators or "curves" begin at time zero with S(t) = 1 and
then decrease in a series of steps corresponding to
observed times of failure.
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Kaplan-Meier Estimators of the Survival Function
(S(t)) for Two Groups (Treatment and Control).
0.8 Controls
0.6
S(t)
Treatment
0.4
0.2
0
0 1 2 3 4 5
Years
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Log-rank test
• a statistical test of the difference in survival distributions
(see Peto et al, 1977).
33
Cox proportional hazard model
• Advantages:
• ability to handle a large number of prognostic variables (both
discrete and continuous)
• can adjust for confounding variables, and
• evaluate interaction effects
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B. Statistical Control of Common
(Selection) Biases
• Prognostic studies are essentially observation
studies that focus on survival (or some other
outcome).
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Table. Methods for Controlling Selection Bias
(from Fletcher)
Phase of Study
Randomization Random assignment ensures that known and unknown +
confounders are equally distributed between exposure groups
(this is rarely feasible however, unless a specific RCT designed
to evaluate some aspect of prognosis is being conducted).
Restriction If a strong confounding factor is known - such as age or sex - +
limit the range of the characteristics of patients in the study.
Matching Match exposure groups on the basis of important prognostic +
variables - such as stage of disease, age or sex.
Stratification Compare event rates within subgroups (strata) with otherwise +
similar probability of outcomes e.g., sex or age-groups specific
rates.
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Table. Adjustment Procedures to Control
Selection Bias
Adjustment Procedures Design Analysis
Simple Mathematically adjust crude rates for a characteristic known to +
be an important prognostic factor e.g., age adjustment.
Multiple Use mathematical models to adjust risk estimates for several +
prognostic variables (Cox Regression).
Sensitivity Analysis Describe how the results could differ by changing the values +
of known prognostic factors over plausible ranges. Best/worst
case analysis is an example.
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V. Ideal Characteristics of Prognostic
Studies
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V. Ideal Characteristics of Prognostic
Studies
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Editorial Readings
• Melton
• What is selection bias? and how can it effect the
conclusions of studies?
• Motulsky
• Why did author place such emphasis on
understanding the selection method?
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VI. Clinical Decision Rules (CDR)
• Outcomes:
• Probability of disease/event (risk)
– e.g., APGAR, APCHE, CVD Risk Prediction (Framingham),
colic prognosis
• Diagnostic/treatment decision
– e.g., Breast biopsy decisions, Breast CA risk (Gail model), colic
surgery
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CDRs – 3 Step Development Process
• Step 1 - Derivation:
• Identify important (predictive) variables
• Use statistical methods (Logistic regression,
recursive partitioning, neural networks), or pick
variables based on expert opinion
• Initial statistical testing (validation)
– Split sample (development and training sets)
– Bootstrap techniques
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CDRs – 3 Step Development Process
• Step 2 – Validation
• Usually prospective, validation required because
– CDR accuracy may be specific to development
population (because of severity & disease prevalence)
– CDR may not be applied in the same manner in other
populations
• Narrow: Application to similar patient popl.
• Broad: Application to different populations with
varying prevalence and disease spectrum.
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CDRs – 3 Step Development Process
• Step 3 – Impact Analysis
• Required because reluctance to use CDR is common. Why?
– Concern about different patient population/settings
– Risk of false negatives (esp. legal concerns)
– Rules are complicated or take too long to use
– Doesn't provide a course of action (just a probability!!)
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CDR - Hierarchy of Evidence
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CDR – Methodological Standards
(McGinn, JAMA 2000)
46
CDR – Methodological Standards
(McGinn, JAMA 2000)
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Thank You