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Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Cipto Mangunkusumo Hospital / Faculty of Medicine UI, Jakarta kuntjoro.harimurti01@ui.ac.id
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Rate of survival
what the numerator and denominator?
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Event
death disease relapse recovery
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Time as an outcome
Survival time:
Leukemia patients/time in remission (weeks) Diabetes patients/time until heart disease (years) Elderly (60+) population/time until death (years) Etc.
From the beginning of follow-up until an event occur, age of individual when an event occur
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Event
Any designated experience of interest that may happened to an individual
Death Disease incidence Relapse from remission Recovery Etc.
Typically refers to failure (negative event: e.g. death, relapse), but may be a positive event (e.g. recovery) Usually only one event is of designated interest; it could be >1 events competing risk
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Censored data
A key analytical problem in survival analysis Censoring occurs when there is some information about individual survival time, but dont know how the survival time exactly Censored data appears because we cannot follow every subjects until an event occurs Three reasons why censoring may occur:
The study end Lost to follow up Withdrawn from the study
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Relapse: Event
Relapse time
Follow-up time
4
T=5
10
12
A
S U B J E C T S
X
T=12 T=3.5
B C D
Censored
Lost followup T=3.5 Censored
E
F
Study start
Event (relapse)
Study end
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Actuarial Method
Used to determine the survival on specific time interval Time interval chosen depends on disease characteristic or effect Conditions and assumption in actuarial analysis:
Beginning of the observation should be clearly defined Effect studied should be clearly defined Withdrawal and loss to follow-up should be independent to effect Risk for experience the effect does not depends on calendar year Risk for experience the effect in chosen interval should be equal Censored patients assumed to experience effect
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
31/12/05
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
We can rearrange the length of observation as if all observations started at the beginning of the study
A B C D E F G H I J K L M N O 1/1/ 01 1/1/ 02 1/1/ 03 1/1/ 04 1/1/ 05 31/12/ 05 A B C D E F G H I J K L M N O 0 1 2 3 4 5
Dates
Years
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Re-arranged data
Study period A B C D E F G H I J K L M N O 0 1 2 3 4 5
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
34; died 57; live at study end 20; died 47; died 2; died 38; died 14; lost to follow-up 23; lost to follow-up 21; died 23; died 12; live at study end 3; died 1; lost to follow-up 3; live at study end 2; live at study end
Ix
cx
dx
Interval (year)
0123-
0.85
0.53 0.40 0.13
4-
0.5
0.13
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
0.8
Probability of survival
0.7
0.6
0.53
0.5
0.4 0.3 0.2 0.1 0 1 2 3
0.13 0.13 0.40
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Some people talks in their sleep. Lecturers talk while other people sleep. (Albert Camus)
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Kaplan-Meier Method
The most common method for survival analysis is Kaplan-Meier (product limit) estimation This technique measures the hazard every time there is an event The rates are based on the number of individuals living at the start of the time interval These counts of living people at risk vary with the number of censored records and number of events Used to estimate the survival curve from observed survival times without the assumption of an underlying probability distribution
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Kaplan-Meier Method
Probability of surviving k or more periods from entering the study is a product of the k observed survival rates for each period (i.e. the cumulative proportion surviving):
S(k) = p1 x p2 x p3 x x pk
S = survival function p = proportion surviving in given period
pi = proportion surviving in a period ri = number alive at the beginning of the period di = number of deaths within the period
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
34; died 57; live at study end 20; died 47; died 2; died 38; died 14; lost to follow-up 23; lost to follow-up 21; died 23; died 12; live at study end 3; died 1; lost to follow-up 3; live at study end 2; live at study end
Ordered data
Study period
M E O L N K G C I H J A F D B 0 365 730 1095 1440 1825
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
length of observation (days) 31; lost to follow-up 60; died 62+; live at study end 86; died 92; live at study end 356; live at study end 410; lost to follow-up 590; died 610; died 680; lost to follow-up 700; died 1050; died 1130; died 1400; died 1704; live at study end
Patient name M E O
Deaths (di)
0
31+ 60 62+ 1 (14-1)/14=0.929 0.929
L
N K G C I H J A F D B
86
92+ 356+ 410+ 590 610 680+ 700 1050 1130 1400 1704+
12
(12-1)/12= 0.917
0.917*0.929=0.852
8 7 5 4 3 2
1 1 1 1 1 1
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Kaplan-Meier Curve
1.0 60 86 590 610 700 1050 1130 1400
0.9
0.8 Probability of survival 0.7 0.6 0.5
* *
* *
0.4
0.3 0.2 0.1 0 1
*
*
2 3 Survival time (Years) 4 5
Example
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Calculation for the Kaplan-Meier estimate of the survival function for the treatment 1
Patient number Survival time (days) 0 6 9 8 12 7 6 1 1 (7-1)/7=0.857 (6-1)/6=0.833 1x0.857=0.857 0.857x0.833=0.714 Number known to be alive (ri) Deaths (di) Proportion surviving (pi=[ri-di]/ri) Cumulative proportion surviving (S[t])
10
12 13 14
15+
25+ 37 55 3 2 1 1 (3-1)/3=0.667 (2-1)/2=0.500 0.714x0.667=0.476 0.500x0.476=0.238
15
72+
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Calculation for the Kaplan-Meier estimate of the survival function for the treatment 2
Patient number Survival time (days) Number known to be alive (ri) 8 8 6 2 1 (8-2)/8=0.750 (6-1)/6=0.833 1x0.750=0.750 0.750x0.833=0.625 Deaths (di) Proportion surviving (pi=[ri-di]/ri) Cumulative proportion surviving (S[t])
0
1 2 3 1 1 4
4
5 7 8
5
6+ 9 9+
5
3
1
1
(5-1)/5=0.800
(3-1)/3=0.667
0.625x0.800=0.500
0.500x0.667=0.333
11
22
(1-1)/1=0
0.333x0=0
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Estimating and comparing survival curve for the two treatment group using the Kaplan-Meier method
1.0 0.9
0.8
Probability of survival
0.7
0.6
Treatment 1
0.5
0.4 0.3 0.2 0.1 0
Treatment 2
20
60
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Comparing survival curves of two groups using the log rank test
Log rank test: a statistical hypothesis test to compare two survival curves Null hypothesis: no difference between the population survival curves It can be calculated manually or by statistical packages computer program
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
O1 and O2 = total numbers of observed events in groups 1 and 2 E1 and E2 = total numbers of expected events
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Yes
Event
No
Group 1
b
d
Group 2
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Survival of patients with bronchiectasis after the first ICU stay for respiratory failure
Dupont et al. Chest 2004;125:1815-20
Objectives of the study: to assess the long term outcomes and to identify the factors associated with a reduced survival on patients with bilateral bronchiectasis admitted for the first time to the ICU for respiratory failure Study period: 10 years (January 1990 to March 2000) retrospectively Time variable: days after ICU admission Event: death
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Survival of patients with bronchiectasis after the first ICU stay for respiratory failure
Dupont et al. Chest 2004;125:1815-20
The KaplanMeier estimates of survival for (a) age > 65 years or 65 years, and (b) long-term oxygen therapy (LTOT) before intensive care unit admission (yes/no). The P values are for the log rank test.
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Survival of patients with bronchiectasis after the first ICU stay for respiratory failure
Dupont et al. Chest 2004;125:1815-20
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Conclusions
Survival analysis provides special techniques that are required to compare risks for event associated with different treatment groups, where the risk change over time In measuring survival time, the start and end-points must be clearly defined and the censored observation noted Actuarial method and Kaplan-Meier provide a method for estimating the survival curve The log rank test provides a statistical comparison of two groups Coxs proportional hazards model allow additional covariates to be included
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital
Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Faculty of Medicine, University of Indonesia Cipto Mangunkusumo Hospital