PERFORMANCE

 OF  UPPER  LIMB  

MEASURE:  PUL  2.0
Tina  Duong

Stanford  University

PPMD  Conference  June  2016

 WHAT  IS  IT?  

• Developed  by  an  international  Clinical  Outcomes  Group  

• Consisting  of  clinicians,  scientists,  patient  advocacy  groups  and  
industries  

• Determine Gaps
• Stage of disease and Clinical Endpoints
• Assessment tool that encompasses spectrum of
disease
 PUL:  FUNCTION  BASED  CONCEPT

Conceptual  Framework 3  dimensions

• Adapted  Screening  tool
• Based  on  continuum  of  functional  
ability  and  natural  history  of  
functional  decline  in  DMD.  
• Movement  is  based  on  functional  
workspace
 DEVELOPMENT  OF  PUL  1.2
• Systematic  Review  for  suitability  of  of  existing  validated  
upper  extremity  measures  (Mazzone et  al)
• Brooke  Upper  extremity  scale
• Upper  Limb  Functional  ability  test
• Jebson Hand  Function  test
• Motor  Function  Measure  (MFM)
• Clinical  Meaningfulness
• Boys  and  their  families  affected  by  DMD  provided  relevance  of  
each  assessments.  

1.  
 SCALE  DEVELOPMENT
•Psychometric  methods:  Rasch  analysis
•Improved  robust  internal  reliability,  validity,  and  hierarchical  
scalability
•Goal:  linearize  measurement  to  have  one  point  change  reflect  
the  same  across  the  breadth  of  scale  regardless  of  ability

2.
 RELIABILITY:  SCALE  DEVELOPMENT  (CONT)
3.

ü Reliability  and  Validity  of  Test  measures

PUL  1.2:  Three  Dimensions:  22  Items   Screening  Item:  
Modified  Brooke  
(Total  score=72)
Scale

4  Items:  Max  score  =16

9  Items:  Max  Score=34

8  Items:  Max  Score:  24

TOTAL  UPPER  LIMB  SCORES  IN  AMBULANT AND  NON  
AMBULANT  DMD  BOYS  AND  ADULTS

N=322
Age  range:  4-­35  years
Mean  age=12  years
 RESULTS

• Excellent  inter  and  intra-­‐observer  reliability  for  

ambulant  and  non-­‐ambulant  population  
• ICC=.96
• Proximal  weakness  able  to  be  detected  in  young  
ambulant  boys.  
• Sensitive  to  capture  the  proximal  to  distal  gradient  of  
weakness  observed  in  DMD
• No  floor  effect
• Suitable  for  assessment  ages  5  years-­‐ adulthood
• Suitable  for  multicentric studies
 CONSTRUCT  VALIDITY:  6MWT

• >400METERS
• N=164;  ICC=.499  (non-­‐linear)
• PUL=70-­‐74  (95%)
• 6MWD=118-­‐557m  
(mean=376m;  SD=90.59) • 300-­‐400  METERS
• PUL  <70  (40%)
• PUL  Score=52-­‐74  
(mean=70.74;  sd=4.66) • PUL  MOST  RELEVANT  FOR  < 300  
METERS
• TRANSITIONAL  OUTCOME
CONCURRENT  VALIDITY:  REACHABLE  WORKSPACE  AND  PUL

• N=53  DMD  (non  amb  =13);  n=24  aged  matched  controls

• Pearson  correlation=-­‐.602  (p<.001)
• Total  Relative  Surface  Area  (RSA)  and  PUL
• Quadrant  RSA  highly  correlated  with  PUL  dimensions
• RSA  able  to  differentiate  PUL  domain  items:  
• Shoulder:  Differentiate  shoulder  flexion,  abduction  
• Elbow:  Hands  to  mouth,  hands  to  table,  Lift  cans,  removing  lid
• Distal:  Picking  up  coins  and  finger  diagram
UPPER  BODY  PATIENT  REPORTED  OUTCOME    MEASURE:  
DMD SPECIFIC

• Developed  by  an  international  Clinical  Outcomes  Group  

• Consisting  of  clinicians,  scientists,  patient  advocacy  groups  and  industries  
• Developed  in  parallel  with  the  PUL
• Developed  based  on  guidelines  from  FDA    and  modern    psychometric  properties,  clinical  
knowledge  and  patient/family  feedback
• 32  items  with  domains  of  activities  of  daily  living  (ADL):  Food,  self-­‐care,  Household  
and  environment,  Leisure  and  communication)
• N=157  from  7  international  centers
• Mean  age  of  16  years  (SD  7,5  years,  range  7-­‐43  years  
• Ambulant=  71;  Non-­‐Ambulant=110
• Reliability  ICC=.99
WHY  PUL  2.0  ?
 • During  development  
process,  changes  have  been  
suggested  to  further  
REFINEMENT
improve  PUL’s  measurement  
properties  and  ease  and  
clarity  of  testing…Leading  to  
PUL  2.0
PUL  1.2 PUL  2.0

Some  of  the  more  difficult  

items  removed  as  
measuring  same  level  of  
ability

Many  items  simplified  

scoring  to  0,  1  and  2  to  
better  reflect  progression  
rather  than  strategies

Removed  two  grip  items  as  

measuring  same  level  of  
ability
COMPARISON  OF  PUL  1.2  AND  PUL 2.0

• RELIABIILTY
• PUL  1.2=.961
• PUL  2.0=.964
• Rasch  analysis  showed  PUL  2.0  shows  improved
• Item  and  fit  with  high  correlation
• Improved  Ordering  and  threshold  response
• Disease  progression  reflects  logical  and  hierarchical  order
PUL  2.0:  Three  Dimensions:  22  Items   Screening  Item:  
(Total  score=  42  (74)) Modified  Brooke  
Scale

4  Items:  Max  score=  12  (16)

9  Items:  Max  Score=  17  (34)

8  Items:  Max  Score=13  (24)

 PUL  1.2  TO  PUL  2.0:  FUTURE  PLANS

• Preparing  publication  on  converting  the  raw  score  on  

one  scale  (PUL1.2)  to  an  equivalent  raw  score  on  
PUL2  Repeating  reliability  on  PUL  2.0
• Already  adopted  for  trials  –
 STUDIES  USING  PUL
Company PUL  1.2 PUL  2.0
Eli  Lilly x
PTC x
Biomarin x
Capricor x
Sarepta x x
CINRG  DMD x
Pfizer x
Fibrogen x
Summit x
CINRG  BMD x
Imaging  DMD x
 CONCLUSIONS
• Currently  being  used  in  both  ambulatory  and  non-­‐ambulatory  clinical  
trials
• Good  reliability  and  expected  improved  reliability  with  PUL  2.0
• Construct  validity  with  6MWT  
• Concurrent  validity  with  Kinect  reachable  workspace
• PUL  and  PROM  developed  based  on  needs  assessment  of  large  DMD  
databases  and  FDA  request  for  clinically  meaningful  outcome  
• Upper  Limb  Patient  Reported  Outcome  Measure    (PROM)  developed  in  parallel  
with  PUL

• Meets  criteria  for  desired  functional  strength  endpoint  measure

• Presented  to  FDA  at  Policy  forum  and  EMA  :  Well  received
• Manuscripts  in  Draft
• PUL  version  1.2  and  2.0  comparison  
• Sensitivity:  Longitudinal  assessment