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

15OCT2013 PhUSE 2013 : IS05 2

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

15OCT2013 3 PhUSE 2013 : IS05

Three Dimensions

Programming Ap$tude

Communica$on Skills

Domain Knowledge

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Three Dimensions

Are these Sufficient?

15OCT2013 5

Fourth Dimension…

PhUSE 2013-‐ IS05

STATISTICS

Case Studies

•  Summary of Efficacy Endpoint

•  Survival Analysis Graph

15OCT2013 6 PhUSE 2013 : IS05

Flow of the Case Study

Background

Problem

Reason

Discussion

Solu$ons

15OCT2013 7 PhUSE 2013 : IS05

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

15OCT2013 8 PhUSE 2013 : IS05

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

15OCT2013 9 PhUSE 2013 : IS05

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

15OCT2013 10 PhUSE 2013 : IS05

15OCT2013 PhUSE 2013 : IS05 11

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

15OCT2013 PhUSE 2013 : IS05 12

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


Problem

Reason

Discussion

Solu$ons

15OCT2013 13 PhUSE 2013 : IS05

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)


Study 123 (EXT) (N=235)



(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%


Problem

Reason

Discussion

Solu$ons

15OCT2013 14 PhUSE 2013 : IS05

1.  Levels incorrectly assigned .


Data:

Back-‐ ground

Problem

Reason

Discussion

Solu$ons

15OCT2013 15 PhUSE 2013 : IS05

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 .


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)


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

15OCT2013 16 PhUSE 2013 : IS05

a. Number of levels :

1.  Levels incorrectly assigned


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)


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

15OCT2013 17 PhUSE 2013 : IS05


What is Exact?



Data :

Back-‐ ground

Problem

Reason

Discussion

Solu$ons

15OCT2013 18 PhUSE 2013 : IS05

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 .




•  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

15OCT2013 19 PhUSE 2013 : IS05

b. Order of levels :

1.  Levels incorrectly assigned :


Re-‐define the Levels

if RELFR = ‘Yes’ then RELFRN = 1;

if RELFR = ‘No’ then RELFRN = 2;

Back-‐ ground

Problem

Reason

Discussion

Solu$ons

15OCT2013 20 PhUSE 2013 : IS05


Problem

Reason

Discussion

Solu$ons

15OCT2013 21 PhUSE 2013 : IS05

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%

15OCT2013 PhUSE 2013 : IS05 22


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;


15OCT2013 23 PhUSE 2013 : IS05


Study 123 (EXT) (N=235)



(0.4829,0.6137) (0.0665,0.1481)


Study 123 (EXT) (N=235)



(0.3775,0.5262) (0.8450,0.9376)

Incorrect Output:

Correct Output:

Back-‐ ground

Problem

Reason

Discussion

Solu$ons


Problem

Reason

Discussion

Solu$ons

15OCT2013 24 PhUSE 2013 : IS05

1.  Restructuring the data.

2.  Handling of the variable of interest with respect to sta$s$cal test.

3.  Change in alpha value.


Problem

Reason

Discussion

Solu$ons

15OCT2013 25 PhUSE 2013 : IS05

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!

15OCT2013 PhUSE 2013 : IS05 26

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

15OCT2013 27 PhUSE 2013 : IS05

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


15OCT2013 28 PhUSE 2013 : IS05

Back-‐ ground

Problem

Reason

Discussion

Solu$ons


15OCT2013 29 PhUSE 2013 : IS05

From: Sta$s$cian To: Programmer Cc: Validator Subject: Review Comments: Figure 1

15OCT2013 PhUSE 2013 : IS05 30

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


15OCT2013 31 PhUSE 2013 : IS05

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


15OCT2013 32 PhUSE 2013 : IS05

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


RATE

Back-‐ ground

Problem

Reason

Discussion

Solu$ons


15OCT2013 33 PhUSE 2013 : IS05

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


Chances of Survival in High Risk group

Chances of Survival

Chances of Survival in Low Risk group

Back-‐ ground

Problem

Reason

Discussion

Solu$ons

15OCT2013 34 PhUSE 2013 : IS05


Back-‐ ground

Problem

Reason

Discussion

Solu$ons

Hazard Rate at which event occurs

Risk &

Time


15OCT2013 35 PhUSE 2013 : IS05

Back-‐ ground

Problem

Reason

Discussion

Solu$ons


15OCT2013 36

Hazard Ra$o Hazard in Group 1

= Hazard in

Reference Group

PhUSE 2013 : IS05

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?


15OCT2013 37 PhUSE 2013 : IS05

Back-‐ ground

Problem

Reason

Discussion

Solu$ons

PROC PHREG DATA = ABC;

MODEL VAR_TIME * VAR_FLAG (0) = GROUP;

RUN;

Censoring Value


15OCT2013 38 PhUSE 2013 : IS05

1. Censoring value

MODEL VAR_TIME * VAR_CENS (0) = GROUP;

RUN;

Back-‐ ground

Problem

Reason

Discussion

Solu$ons

CLASS GROUP (REF = ‘HIGH’);


15OCT2013 39 PhUSE 2013 : IS05

2. Order of the Grouping variable

PROC PHREG DATA = ABC;

Back-‐ ground

Problem

Reason

Discussion

Solu$ons


15OCT2013 40 PhUSE 2013 : IS05

•  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


15OCT2013 41 PhUSE 2013 : IS05

Points to Remember

Consult study sta$s$cian

15OCT2013 42 PhUSE 2013 : IS05

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

15OCT2013 43 PhUSE 2013 : IS05

15OCT2013 PhUSE 2013 : IS05 44

Three Dimensions

Are these Sufficient?

15OCT2013 45

STATISTICS AS THE “FOURTH” DIMENSION IS NECESSARY!!!

PhUSE 2013 : IS05

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

15OCT2013 46 PhUSE 2013 : IS05

15OCT2013 PhUSE 2013 : IS05 47

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

15OCT2013 48 PhUSE 2013 : IS05

THANK YOU

Email Address

Gauri Khatu

[email protected]

Vibhavari Inamdar

[email protected]

15OCT2013 49 PhUSE 2013 : IS05

stascs - lex jansen7/10/2013 vi open summary’of’eﬃcacy’endpoint ’ back’ ground’...

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