Stascs - Lex Jansen7/10/2013 VI Open Summary’of’Efficacy’Endpoint ’ Back’ ground’...
Transcript of Stascs - Lex Jansen7/10/2013 VI Open Summary’of’Efficacy’Endpoint ’ Back’ ground’...
Sta$s$cs Fourth Dimension of a “Sta$s$cal”
Programmer
Gauri Khatu, Cytel
Vibhavari Inamdar, Cytel
Sta$s$cs Fourth Dimension of a “Sta$s$cal” Programmer
Gauri Khatu, Cytel Vibhavari Inamdar, Cytel
Session IS05 -‐ PhUSE 2013
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Disclaimer
This presenta$on is based on first-‐hand experience of the presenters, their opinions and learnings.
However this is not to be construed as an official statement endorsed by Cytel
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Three Dimensions
Programming Ap$tude
Communica$on Skills
Domain Knowledge
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Three Dimensions
Are these Sufficient?
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Fourth Dimension…
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STATISTICS
Case Studies
• Summary of Efficacy Endpoint
• Survival Analysis Graph
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Flow of the Case Study
Background
Problem
Reason
Discussion
Solu$ons
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Table 1.1.2
Proportion of Subjects who are relapse free by Study
Safety Population: Subjects Randomized to Placebo in Study123 and to Dose A in
Study 123 (EXT)
Characteristic Statistics Study 123
(N=xx) Study 123 (EXT)
(N=xx)
Relapse-Free Subjects Yes xx xx
No xx xx
Total xx xx
Exact 97.5 % CI for proportion of Relapse-free subjects (x.xx,x.xx) (x.xx,x.xx)
Case Study 1 Summary of Efficacy Endpoint
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Summary of Efficacy Endpoint
• Therapeu$c Area : Neurology • Disease : Mul$ple Sclerosis • Phase : III • Study Design : Randomized, Placebo-‐controlled,
Extension of Study 123 • Study Name : Study 123 (EXT) • Efficacy Endpoint : Relapse Free Status • Task Assigned : To calculate propor$on of relapse free
subjects for study 123 and study123(EXT) by using binomial distribu$on.
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Table 1.1.2 Proportion of Subjects who are relapse free by Study Safety Population: Subjects Randomized to Placebo in Study123 and to Dose A in Study 123 (EXT)
Characteristic Statistics Study 123
(N=xx) Study 123 (EXT)
(N=xx) Relapse-Free Subjects Yes xx xx
No xx xx Total xx xx
Exact 97.5 % CI for proportion of Relapse-free subjects (x.xx,x.xx) (x.xx,x.xx)
Summary of Efficacy Endpoint Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Programmer : Hey! The table is ready for valida$on. It was very simple. Just the counts and CIs.
Validator: Oh great ! I will validate and send you the findings.
Chat between Programmer & Validator
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Programmer :Yeah! But I don’t think there should be any valida$on findings . It was a very trivial job!
Validator: Ok. That's good!
Chat between Programmer & Validator
Valida$on Finding: Issue # Table
name Issue Category Descrip$on of Issue Date &
ini$al Status
1 Table 1.1.2 Value not matching
Counts match. But CI’s don’t match
7/10/2013 VI Open
Summary of Efficacy Endpoint Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Characteristic Statistics Study 123 (N=235)
Study 123 (EXT) (N=235)
Relapse-Free Subjects
Exact 97.5 % CI for proportion of Relapse-free subjects
(0.4829,0.6137) (0.0665,0.1481)
Characteristic Statistics Study 123 (N=235)
Study 123 (EXT) (N=235)
Relapse-Free Subjects
Exact 97.5 % CI for proportion of Relapse-free subjects
(0.3775,0.5262) (0.8450,0.9376)
Programmer’s Table:
Validator’s Table:
1. Levels incorrectly assigned. -‐Number and order of the levels 2. CI’s wrongly calculated. -‐Required CI : 97.5 % -‐Derived CI : 95%
Summary of Efficacy Endpoint Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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1. Levels incorrectly assigned .
Summary of Efficacy Endpoint
Data:
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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SUBJID STUDY RELFR 101 1 Yes 101 2 Yes 103 1 No 103 2 Yes 105 1 . 105 2 . 106 1 No 106 2 .
a. Number of levels : 3 Levels • Yes • No • Missing
1. Levels incorrectly assigned .
Summary of Efficacy Endpoint
Table 1.1.2 Proportion of Subjects who are relapse free by Study Safety Population: Subject Randomized to Placebo in Study123 and to Dose A in Study 123 (EXT)
Characteristic Statistics Study 123 (N=235)
Study 123 (EXT) (N=235)
Relapse-Free Subjects Yes 106 211
No 129 24 Total 235 235
Exact 97.5 % CI for proportion of Relapse-free subjects (0.4829,0.6137) (0.0665,0.1481)
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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a. Number of levels :
1. Levels incorrectly assigned
Summary of Efficacy Endpoint
Table 1.1.2 Proportion of Subjects who are relapse free by Study Safety Population: Subject Randomized to Placebo in Study123 and to Dose A in Study 123 (EXT)
Characteristic Statistics Study 123 (N=235)
Study 123 (EXT) (N=235)
Relapse-Free Subjects Yes 106 211
No 129 24 Total 235 235
Exact 97.5 % CI for proportion of Relapse-free subjects (0.4829,0.6137) (0.0665,0.1481)
Test : Fisher’s Exact
Binomial
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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a. Number of levels :
What is Exact?
1. Levels incorrectly assigned
Summary of Efficacy Endpoint
Data :
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Remove Missing
SUBJID STUDY RELFR 101 1 Yes
101 2 Yes 103 1 No 103 2 Yes 105 1 . 105 2 . 106 1 No 106 2 .
a. Number of levels :
1. Levels incorrectly assigned
Summary of Efficacy Endpoint
• Required:
• SAS Procedure : Proc Freq
NO YES
Sequence of Variable: RELFR
Propor$on calculated for “NO”
Propor$on of Relapse Free Subjects
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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b. Order of levels :
1. Levels incorrectly assigned :
Summary of Efficacy Endpoint
Re-‐define the Levels
if RELFR = ‘Yes’ then RELFRN = 1;
if RELFR = ‘No’ then RELFRN = 2;
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Summary of Efficacy Endpoint Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Recap of the Reason:
1. Levels incorrectly assigned. a. Number of levels b. Order of levels
2. CI’s wrongly calculated. Required CI : 97.5 % Derived CI : 95%
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Summary of Efficacy Endpoint
2. Confidence Intervals wrongly calculated : • Default CI in Proc FREQ is 95% • Task: To Calculate 97.5%
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
PROC FREQ DATA = ABC;
TABLES RELFR/BINOMIAL ;
RUN;
ALPHA=0.025;
Summary of Efficacy Endpoint
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Characteristic Statistics Study 123 (N=235)
Study 123 (EXT) (N=235)
Relapse-Free Subjects
Exact 97.5 % CI for proportion of Relapse-free subjects
(0.4829,0.6137) (0.0665,0.1481)
Characteristic Statistics Study 123 (N=235)
Study 123 (EXT) (N=235)
Relapse-Free Subjects
Exact 97.5 % CI for proportion of Relapse-free subjects
(0.3775,0.5262) (0.8450,0.9376)
Incorrect Output:
Correct Output:
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Summary of Efficacy Endpoint Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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1. Restructuring the data.
2. Handling of the variable of interest with respect to sta$s$cal test.
3. Change in alpha value.
Summary of Efficacy Endpoint Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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1. Restructuring the data.
2. Handling of the variable of interest with respect to sta$s$cal test.
3. Change in alpha value.
Sta$s$cal Background Missing!
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Case Study 2 Survival Analysis Graph
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
Therapeu$c Area : Cardiology Phase : II Study Design : Randomized, Parallel Event : Death due to Myocardial Infarc$on Groups : Low and High risk groups Task Assigned : To plot Kaplan Meier survival curve and calculate the Hazard ra$o with reference
to the High risk group to study survival in the two popula$on groups
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Low Risk High Risk
0 5 10 15 20 25 30 35
Time in Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Proba
bility
HR = 4.18 p-‐value <0.0001
Figure 1: Kaplan Meier Survival Graph Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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From: Sta$s$cian To: Programmer Cc: Validator Subject: Review Comments: Figure 1
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What went wrong?
• Incorrect numbers presented on graph
• Mistake not caught during valida$on
Programmer Sta$s$cian
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
• Lack of awareness about the Sta$s$cs behind the numbers
Survival Analysis Graph
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Low Risk High Risk
0 5 10 15 20 25 30 35
Time in Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Proba
bility
HR = 4.18 p-‐value <0.0001
Kaplan Meier Survival Graph
Death
Censored
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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Low Risk High Risk
0 5 10 15 20 25 30 35
Time in Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Proba
bility
HR = 4.18 p-‐value <0.0001
Kaplan Meier Survival Graph
RATE
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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1 Month 6 Months
Low Risk High Risk
0 5 10 15 20 25 30 35
Time in Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Proba
bility
HR = 4.18 p-‐value <0.0001
Kaplan Meier Survival Graph
Chances of Survival in High Risk group
Chances of Survival
Chances of Survival in Low Risk group
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
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Survival Analysis Graph
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Hazard Rate at which event occurs
Risk &
Time
Survival Analysis Graph
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Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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Hazard Ra$o Hazard in Group 1
= Hazard in
Reference Group
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Survival Hazard
Survival Hazard
Low Risk Group
High Risk Group
Task: Hazard ra$o with reference to the High risk group to study survival in the two groups
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Low Risk High Risk
0 5 10 15 20 25 30 35 Time in Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Proba
bility
HR = 4.18 p-‐value <0.0001
Figure 1: Kaplan Meier Survival Graph
Why?
Survival Analysis Graph
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Back-‐ ground
Problem
Reason
Discussion
Solu$ons
PROC PHREG DATA = ABC;
MODEL VAR_TIME * VAR_FLAG (0) = GROUP;
RUN;
Censoring Value
Survival Analysis Graph
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1. Censoring value
MODEL VAR_TIME * VAR_CENS (0) = GROUP;
RUN;
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
CLASS GROUP (REF = ‘HIGH’);
Survival Analysis Graph
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2. Order of the Grouping variable
PROC PHREG DATA = ABC;
Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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• Appropriate value in the sta$s$cal procedure
• Defini$on of the reference group
Low Risk High Risk
0 5 10 15 20 25 30 35
Time in Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Proba
bility
HR = 0.24 p-‐value <0.0001
Figure 1: Kaplan Meier Survival Graph Back-‐ ground
Problem
Reason
Discussion
Solu$ons
Survival Analysis Graph
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Points to Remember
Consult study sta$s$cian
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Understand the sta$s$cal background, inves$gate, research and learn
Recap
Efficacy Analysis
• Restructuring the data. • Handling of the variable of interest with respect to the sta$s$cal test.
• Change in alpha value. Survival Analysis graph
• Interpreta$on of Kaplan Meier plots and Hazard Ra$o
• Appropriate method to compute the Hazard ra$o
• Inter-‐rela$on between Survival plot and HR
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Three Dimensions
Are these Sufficient?
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STATISTICS AS THE “FOURTH” DIMENSION IS NECESSARY!!!
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Basic sta$s$cal knowledge
ü A compe$$ve edge over a pure SAS programmer
ü Take decisions while programming
ü Jus$ce to the role
Conclusion
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Online Help
• sta$s$cs.com
• Probability & Sta$s$cs | Open Learning Ini$a$ve
• Sta$s$cs Tutorial
• www.sta$s$cs-‐help-‐online.com/node53.html
• INTRODUCTORY STATISTICS -‐ FREE Online Course
• www.micquality.com/introductory_sta$s$cs
• www.math.leidenuniv.nl/statscience
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THANK YOU
Email Address
Gauri Khatu
Vibhavari Inamdar
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