Improving Mobility in Peripheral Artery Disease Using an Ankle Foot Orthosis
Phase: NA
Conditions: Peripheral Artery Disease
Sponsor: University of Nebraska

Improving mobility in peripheral artery disease using an ankle foot orthosis 
NCT02902211 
06/01/2020 

1.  Specific  Aims  
Peripheral   artery   disease   (PAD)   is   a   common   cardiovascular   disease   manifesting   from   atherosclerotic  
blockages  in  the  arteries  of  the  legs.  The  most  prevalent  symptom  of  PAD  is  intermittent  claudication,  defined  
as  pain  or  discomfort  in  the  legs  that  is  produced  by  physical  activity  and  is  relieved  only  through  rest.  PAD  
results  in  significant  functional  limitations  such  as  slower  walking  velocity  and  an  overall  sedentary  lifestyle1-­5.  
Our   research   has   documented   significant   deficits   in   gait   biomechanics;;   specifically,   an   inability   of   the   ankle  
plantarflexors  to  generate  normal  torque  and  power6-­10.  Furthermore,  we  found  that  insufficient  blood  flow  is  not  
the   only   mechanism   contributing   to   gait   dysfunction   in   patients   with   PAD11,   12,   but   the   affected   muscle   also  
demonstrates   a   myopathy   that   prevents   normal   leg   function   in   these   patients13-­17.   Thus,   treatment   must  
consider  muscular  function  and  hemodynamics  to  improve  function  and  increase  activity  levels.  
  
Supervised  treadmill  walking  exercise  is  an  effective  treatment  for  increasing  the  distances  patients  with  PAD  
can  walk  18-­21.  However,  there  is  a  critical  treatment  gap  for  individuals  whose  disease  presentations  warrant  a  
non-­operative   treatment   plan   but   lack   the   motivation,   time,   access   and   monetary   resources   for   supervised  
therapy.   An   ankle-­foot   orthosis   (AFO)   to   offset   ankle   plantarflexor   torque   and   power   deficiency   is   a   novel  
approach  to  increase  the  walking  distances  and  physical  activity  levels  in  those  with  PAD.  Made  of  a  carbon-­
composite  material,  AFOs  are  adjustable,  affordable  and  could  be  prescribed  and  worn  long-­term  to  overcome  
the   reduced   propulsion   and   improve   walking   economy22-­26.   The   spring-­like   properties   of   carbon-­composite  
AFOs   allow   energy   storage   at   weight   acceptance   and   return   at   the   point   of   toe   off,   when   the   ankle  
plantarflexors   are   supposed   to   propel   into   the   next   step27,   28.   Improvements   in   ankle   kinetics   and   angular  
momentum  have  been  reported  by  using  an  AFO  with  stroke,  and  other  neuromuscular  disorders  affecting  the  
legs22-­25.  However,  AFOs  are  typically  worn  for  foot  drop,  and  have  never  been  implemented  in  patients  with  
PAD  to  improve  forward  propulsion.  Our  pilot  work  has  shown  that  walking  with  an  AFO  instantly  increases  the  
initial  and  absolute  walking  distances  in  patients  with  PAD  as  much  as  pharmacotherapy  for  six  months29.  An  
AFO   addresses   both   the   myopathy   and   low   blood   flow   problems   associated   with   claudication.   Mechanical  
force  from  the  AFO  compensates  for  the  insufficient  propulsion  force  of  the  myopathic  gastrocnemius  muscles,  
while  at  the  same  time  decreasing  blood  flow  demand  and  muscular  stress  effects  of  ischemia.  Thus  an  AFO  
allows  patients  to  walk  longer  without  pain  or  walk  the  distance  needed  to  complete  daily  activities  with  less  
stress  to  the  affected  leg,  and  may  preserve/improve  the  overall  health  of  the  PAD  limb  by  lowering  oxygen  
demands  to  PAD  muscle  and  effort  induced  ischemia  and  stress.  
  
Hypothesis:   An   AFO   improves   walking   performance   in   patients   with   PAD   by   reducing   the   energy   cost   of  
walking  and  these  improvements  can  be  seen  from  the  first  time  the  patient  uses  the  AFO.  Further,  an  AFO  
intervention  improves  walking  performance  by  improving  the  muscular  function  of  patients’  affected  legs.  
  
Specific   Aim   1:   Test   the   hypothesis   that   from   its   first   use   an   AFO   produces   improvements   in   walking  
performance  of  patients  with  PAD  by  decreasing  the  required  muscle  contribution  and  energy  cost  of  walking.  
  
Specific  Aim  2:  Test  the  hypothesis  that  using  an  AFO  for  three  months  leads  to  progressive  improvements  in  
walking  performance,  physical  activity  levels  and  quality  of  life  of  patients  with  PAD  and  that  these  
improvements  correlate  with  improvements  in  the  morphometric  measurements,  oxygenation  levels,  and  
muscle  strength  and  endurance  characteristics  of  the  affected  legs.  We  will  use  a  crossover  design,  in  which  
half  of  subjects  will  complete  a  three-­month  control  period  before,  and  half  after,  the  AFO  intervention.  
  
Specific   Aim   3:   To   determine   the   feasibility   of   a   three   month   AFO   intervention   by   examining   acceptability  
(satisfaction,  intent  to  continue  use),  demand  (actual  use,  perceived  demand),  implementation  (degree  of  use,  
success  or  failure  of  use,  factors  affecting  use),  and  practicality  (effects,  ability  of  participants  to  use  AFO).  
  
If  our  hypothesis  is  correct,  will  be  the  first  to  demonstrate  that  a  simple,  accessible  AFO  device  can  rapidly  
improve   functional   status   and   quality   of   life   in   patients   with   PAD   immediately   by   decreasing   the   required  
muscular  contribution  and  oxygen  demands  to  PAD  muscle.  Additionally,  Aim  #2  will  evaluate  the  long-­term  
effects  of  wearing  an  AFO  on  functional  status  and  quality  of  life.  Aim  #3  will  help  the  investigative  team  ensure  
it  is  feasible  to  implement  the  AFO  in  our  target  population.  Detailed  measures  of  mechanisms  related  with  
walking  performance,  muscle  contribution,  physical  activity,  quality  of  life  and  how  these  mechanisms  change  
after  wearing  the  AFO  for  three  months  will  provide  the  evidence  required  to  implement  an  AFO  therapy  that  
will  improve  functional  status  and  quality  of  life  in  individuals  with  PAD.  

2. Significance 
Current treatments for PAD do not compensate for muscle myopathy  
Lower extremity peripheral artery disease (PAD) is a prevalent atherosclerotic syndrome that produces 
progressive narrowing and occlusion of the arteries supplying the legs5. PAD affects approximately 8 million 
people in the US, producing a considerable public health burden30. Most PAD patients are older adults and in 
populations older than 70 years the prevalence of PAD increases to 20%5. The cardinal manifestation of PAD 
is claudication, a severe functional limitation identified as gait dysfunction and painful tightness or cramping in 
the muscles of the leg caused by walking and relieved by rest. The prevalence of claudication is expected to 
rise due to the anticipated aging of the population and there is a clear and unmet need for effective treatment31. 
The standard therapies for claudication include pharmacotherapy, supervised exercise therapy, endovascular 
revascularization (angioplasty/stenting) and open revascularization (bypass operations)9. The two medications 
currently approved for the treatment of claudication in the US are pentoxifylline (a methylxanthine derivative) 
and cilostazol (a phosphodiesterase type 3 inhibitor). Both medications have modest efficacy and a recent 
systematic review concluded that pentoxifylline and cilostazol are associated with improvement in maximal 
treadmill walking distance of only 15% and 25%, respectively32. 
Supervised exercise therapy is more effective but unfortunately 
is associated with poor compliance. Moreover, Medicare and 
most medical insurance companies do not pay for exercise 
therapy, limiting access to it. Finally, endovascular and open 
revascularization offer greater degrees of improvement but are 
associated with considerable morbidity and poor long term 
patency40, 41 (Table1). These treatments all require time to take 
effect (3-6 months for pharmacotherapy and exercise), or 
require time for recovery (at least 3 months for endovascular 
and open revascularization procedures). Furthermore, all 
available treatments primarily target the blood flow limitation of PAD while very little is done for the ischemic 
myopathy in the legs of patient with PAD, which has been shown to be a key determinant of decreased walking 
performance in patients with PAD42, 43.  
 
Our research has documented significant deficits in gait biomechanics in patients with PAD compared with 
healthy, aged matched controls. Our studies show that PAD results in inability of the posterior calf muscles, the 
ankle plantarflexors, to generate normal torque and power by the lower extremity joints6-10. We have also 
shown that in PAD gait dysfunction is not only a result of inadequate 
blood flow11, 12, but also the product of an ischemic myopathy affecting the leg muscles of patients with PAD13-
17, 44. An AFO can immediately provide mechanical compensation for ankle plantarflexor torque and power 
deficiency through energy storage and return (Figure 1). Made of a carbon-composite material (Figure 2), off 
the shelf AFOs are adjustable, affordable and could be prescribed to overcome reduced propulsion and 
improve walking economy22-26. The spring-like properties of carbon-composite AFOs allow energy storage at 
weight acceptance and returns at the point of toe off, when the ankle plantarflexes and power is required to 
Treatment 
% Increase In Maximum 
Walking Distance 
Refs 
Pentoxifylline 
15% 
32 
Cilostazol 
25% 
32 
Ramipril 
123% 
33 
Supervised 
exercise 
120% 
34, 35 
Endovascular 
revascularization 
90% 
36-38 
Open 
bypass 
revascularization 
172% 
39 
Table 1. Effects of treatment on absolute 
walking distance. 
Figure 1. The ankle plantarflexors 
contribute 
torque 
during 
the 
propulsion phase at the end of 
stance. 
This 
diagram 
illustrates 
required plantarflexor force during 
normal walking (top) and while 
walking with an AFO (bottom). The 
red 
arrows 
represent 
reduced 
plantarflexor force contribution with 
the AFO. The AFO contributes to 
torque at the end of propulsion is 
shown by bending during weight 
acceptance, which stores energy in 
the carbon composite material that is 
later released during propulsion. The 
moment generated by the AFO is 
equal to the AFO stiffness (k) times 
the change in the AFO angle (). 

propel the body into the next step. AFO devices have stimulated excitement in regards to their potential for 
improving walking performance in individuals with movement disability. In 
individuals with stroke, hemiplegia, and other motor disorders22-25 that have 
inadequate lower extremity torque and power during walking, an AFO has been 
shown to help restore walking performance26, 28, 45. The AFO can similarly be 
used to address this need of a non-operative, efficacious intervention that 
directly increases the functional status in patients with PAD. The results of such 
an intervention on muscle performance, physical activity levels, and quality of 
life present mechanistic research questions that can improve the care of 
patients with PAD.  
 
Objective of our application and significance of proposed work:  
An AFO can directly increase the distance patients with PAD can walk: 
Patients with PAD are limited in the distance they can walk and also 
demonstrate increased energy costs of walking compared with healthy aged-
matched individuals46-49. We will test whether wearing an AFO can instantly 
improve the functional status of patients with PAD. Walking performance will 
be assessed using walking distances, and lower extremity torque and power 
contribution measured by gait biomechanics. Interventions often target blood 
flow improvements in patients with PAD, but the AFO takes a different 
approach by addressing both the blood flow limitation and the myopathy of PAD legs. The AFO can reduce 
ischemia by decreasing the demand for blood flow during walking and can also compensate for myopathy-
related muscle weakness by providing propulsion torque at the end of stance. Previous studies in elderly and 
patients with neuromuscular diseases show that an AFO maintains the overall ankle torque and power profile 
by allowing a reduction in the contribution needed from ankle plantarflexor muscles. We hypothesize that the 
use of an AFO will improve the walking distances of patients with PAD by reducing the energetic requirements 
of the myopathic PAD legs and the energy cost of walking.  
 
Patients wearing an AFO device for three months will progressively improve walking performance and increase 
physical activity levels. The work of our group and others demonstrates that a state of repetitive cycles of 
exercise-induced ischemia followed by reperfusion at rest is associated with episodes of claudication and 
contributes to the muscle degeneration and possibly even the excess morbidity and mortality seen in these 
patients15, 17, 50, 51. It is possible that treating a claudicating patient with an AFO decreases the severity of these 
ischemia/reperfusion events and results in local protection to the treated leg and its muscles and the body as 
whole. If this hypothesis is correct then we can expect that treatment with the AFO may improve the muscle 
histological and biochemical characteristics, muscle strength and performance, walking distances and overall 
activity levels21. 
 
Patients with PAD are sedentary compared with their healthy peers, and this sedentary lifestyle is associated 
with faster declines in functioning and adverse calf muscle changes52-54. Thus, the goal of the proposed AFO 
intervention is to reverse this negative cycle by increasing the ability of patients with PAD to walk. The distance 
that older individuals can walk is directly correlated with muscle strength and ankle plantarflexor torque 
generation. Additionally, the mitochondrial function and oxidative capacity of the plantarflexor muscles of older 
individuals is more affected by physical activity levels than age.55, 56 Therefore, enabling individuals to walk 
more could promote increases in muscle strength and endurance, muscle morphometric measurements, and 
improvements in muscle oxygenation levels, which translate to overall increased walking performance, 
physical activity levels, and quality of life. The concept that patients with PAD will walk more with the AFO is 
based on the premise that wearing the AFO will prolong the onset of pain and results in fewer occurrences of 
claudication pain throughout the day.   
 
Little work has been done to enhance adherence to treatment in PAD  
Adherence to treatment is a critical component to the efficacy of any intervention. Without adherence, even an 
effective intervention has no impact. Thus feasibility measures are warranted when testing the utility of a new 
intervention technique to assess patients’ acceptability (satisfaction, intent to continue use), demand 
(perceived demand), implementation (degree of use, success/failure of use, factors impacting use), and 
practicality (positive/negative effects, ability of participants to use) of the treatment. Research in several fields 
has examined the efficacy of braces and other devices to improve health outcomes. For example, Armstrong 
Figure 2. Carbon-composite 
ankle-foot 
orthosis. 
The 
spring-like 
properties 
of 
carbon 
composite 
allows 
energy to be stored during 
heel strike and returned at 
the point of toe-off. 

and colleagues (2003)57 examined diabetic patients’ adherence to a pressure off-loading device used to treat 
foot ulcerations. They found patients had minimal wear time which partially explained the poor results of the 
study. While the authors speculated on why adherence was low, there was no information on the reasons for 
low adherence from the patients’ perspective. Gathering information from the patients’ point of view is 
necessary to understand whether a new treatment is feasible for patients. Unfortunately little is known about 
how individuals with PAD adhere to treatment. Assessing the feasibility of a new treatment is crucial to its 
application in future studies and can determine if additional educational interventions to improve adherence are 
needed58. In individuals with PAD, walking exercise is a good example of an effective treatment that has been 
difficult to get patients to adopt unless it is supervised. In previous studies of supervised exercise that 
demonstrated increases in walking distances, non-supervised control groups did not show improvements. 20, 59, 
60 There are likely many factors that play a role in non-adherence, including leg symptoms, feelings of 
decreased mobility, low motivation, and low self-efficacy, ones’ belief in his or her capacity to execute the 
desired behavior change61. In studies of exercise adherence in elderly individuals, pain is the top reason for 
non-adherence. 62 It could be assumed that symptomatic claudication pain is also the top reason in patients 
with PAD. Research in individuals with PAD has shown that self-efficacy plays a vital role in adherence to 
exercise. 63, 64 Thus, decreasing the onset of pain through an AFO is likely to help patients address the number 
one barrier to exercise. The lack of improvement in non-supervised individuals emphasizes the need for 
developing interventions that will be adapted by the patients. Additional work to determine treatment 
adherence barriers in individuals with PAD is limited due to lack of additional conservative therapies in this 
group. Thus, the third specific aim will seek to ensure the AFO device is something that will be adapted by 
patients. Patient interviews will capture information on the feasibility of the AFO intervention by capturing 
acceptability, demand, implementation, and practicality. We will use this information to inform modifications to 
the device itself or ways to implement it in patients with PAD. 
 
Improvements in gait and ankle kinetics have been reported by using an AFO in individuals with neurological 
disorders and in the elderly. However, an AFO has never been used to help the gait deficiencies of patients 
with PAD. In this study, we will determine whether wearing a carbon composite AFO leads to a clinically 
important improvement in walking performance, examine changes in walking performance, physical activity, 
and quality of life following a three month intervention, and investigate multiple facets of the intervention to 
improve patient compliance. We propose that these immediate walking performance improvements are the 
result of reduced energy costs for those wearing the device, as previous studies have demonstrated the device 
replaces ankle torque and power. 22-25 Further we propose the mechanisms of improved morphometric 
parameters, muscle oxygenation, and muscle strength and endurance of the affected legs facilitate 
improvements seen following the intervention. 
 
3. Innovation 
The resources of our research group are focused on interventions to improve leg function in patients with PAD 
and we have developed a history of effective patient recruitment and collection of gait data before and after 
therapeutic intervention. Consequently, we have a unique capability to study the effects of interventions on 
walking performance, along with the mechanisms behind those effects. We have actualized this capability by 
coupling our expertise in biomechanics and behavioral intervention with extensive clinical expertise. The result 
is a well-rounded team of scientists equipped for evaluating and refining a new intervention that has great 
potential to impact functional status and quality of life in patients with PAD. Our findings that the ankle 
plantarflexor muscles are the most consistently and greatly affected muscles, combined with our work 
demonstrating muscles of these patients fail at the histological and biochemical levels, have directed us to a 
novel yet simple intervention that can assist these muscles. We see the AFO as a way to address the 
problems of insufficient blood flow and muscular myopathy to enable performance of normal daily activities. 
 
Most conservative approaches to treatment have involved some form of supervised exercise. While exercise 
therapy can be effective in improving the distance patients can walk, it does not have an immediate impact. 
Implementing the simple yet novel intervention of a carbon composite AFO, our study will test the mechanisms 
contributing to both acute and long-term improvements in walking performance, and provide the evidence 
required to successfully implement the AFO as a therapy in this population. This project will provide the 
evidence needed to introduce an easily accessible intervention that can be utilized in the clinical setting. 
Furthermore, our findings will be used to develop additional rehabilitation studies aimed to improve muscle 
health and function in PAD.  
 

4. Approach 
Preliminary work demonstrates forward propulsion is deficient in individuals with PAD. 6-8, 10, 65  
We have conducted several studies evaluating ground reaction forces (Figure 3), joint angle kinematics, and 
joint muscular responses (joint torques) and their contributions (joint powers) during the stance phase of gait in 
patients with PAD.  
In the first study, we compared ground reaction 
forces of 14 patients with PAD (Age: 58 ± 3.4 
years; Body Mass: 81.0 ± 15.64 kg) to five healthy 
controls (Age: 53 ± 3.4 years; Body Mass: 87.4 ± 
12.75 kg)65. In this study we analyzed ground 
reaction forces. Additionally, we evaluated stance 
time and time spent in double-limb support. Results 
demonstrated that in the anterior-posterior force 
direction, the propulsion forces used for push-off in 
late stance were significantly decreased in patients 
with PAD (Figure 3). Regarding stance time and 
time spent in double support, patients with PAD 
had significantly increased values compared with 
healthy controls. All of these differences were even 
present during a pain free (rested) state in patients 
with PAD.  
In several follow-up studies in patients with PAD, 
we evaluated joint muscular responses and their 
contributions by calculating joint torques and 
powers of the ankle, knee, and the hip during 
walking (Figure 4).  
 
The first such study evaluated lower extremity 
joint torques in 13 patients with PAD who 
exhibited bilateral intermittent claudication (Age: 
64.5 ± 8.57 years; Body Mass: 80.7 ± 12.64 kg) 
and 11 healthy control subjects (Age: 66.2 ± 
9.22; Body Mass: 77.8 ± 10.75 kg). 
The conditions included walking prior to the onset of claudication pain and walking after the onset of pain10. 
Compared to controls, patients with PAD had significantly decreased hip extensor torque during early stance in 
both conditions. During the pain condition, patients with PAD had significantly decreased ankle plantarflexor 
torque during late stance. We conducted a follow-up study in 20 patients bilateral PAD (Age: 60.3 ± 7.21 years; 
Body Mass: 82.6 ± 18.05 kg) and 16 healthy controls (Age: 62.8 ± 12.01; Body Mass: 81.8 ± 20.99 kg) that 
evaluated joint torques and also joint powers7, which was the first study to investigate joint powers in patients 
with PAD. Patients were assessed while walking before and after the onset of claudication pain. Patients with 
Figure 4. Average decreases in 
joint power contributions during 
each phase of stance in patients 
with PAD compared with healthy 
controls from previously published 
studies6-8, 10. There are significant 
average decreases at all three 
joints during various phases of 
stance in individuals with PAD. In 
another group of individuals with 
decreased ankle torque and power 
at the end of stance, healthy older, 
the hip compensates by increasing 
the hip extensor torque during 
weight acceptance. As is evident in 
this figure, individuals with PAD do 
not compensate in this way.   
Figure 3. Anterior-posterior (front-to-back) ground reaction 
force curves for patients with PAD prior to the onset of 
claudication (PRE) and following the onset of claudication 
(POST); and healthy controls (CONTROL). Decreased peak 
propulsion towards the end of the stance phase in the PAD 
group is consistent with inability of the ankle plantarflexor 
muscles to generate force to propel individuals into the next 
step just before the toe comes off the ground. This decrease 
occurs prior to the onset of pain and worsens slightly during 
the PAD POST condition.  

PAD had significantly decreased hip and knee power during early stance due to decreased torques produced 
by the hip and knee extensors. Knee and hip power was also significantly decreased during midstance, which 
is attributed to decreased torques produced by the knee extensors and the hip flexors. During late stance, 
reduced propulsion was noted by a significant reduction in the ankle plantarflexor torque and power. All of 
these reductions in patients with PAD were present prior to and after the onset of claudication pain.  
 
We have also performed a similar biomechanical evaluation in 12 unilateral patients with PAD (Age: 61.7 ± 
10.53 years; Body Mass: 84.7 ± 20.24 kg and 10 healthy controls (Age: 66.3 ± 9.22; Body Mass: 77.9 ± 10.65 
kg)8. Results of this study further confirmed the deficiencies of the ankle plantarflexors in propelling the body 
forward, as ankle plantarflexor torque was significantly reduced in the affected limb as compared with controls 
before and after the onset of claudication pain. Additionally, ankle plantarflexor power was significantly 
decreased on both affected and unaffected limbs of patients with PAD as compared to controls. Although ankle 
torque and power are often reduced in healthy older individuals, older compensate by increasing the hip 
extensor torque and power66. Here, the PAD group experiences deficits at the ankle, knee, and the hip rather 
than compensating with a different joint like we see in healthy older individuals. In sum, we estimate that 
average reductions in joint torques during each phase of stance from all of our previous studies are 24% 
decrease in hip power generation during early stance, 39% decrease in knee power generation during 
midstance, and 26% reduction in ankle plantarflexor power generation during late stance as compared with 
healthy controls (Figure 4) 6-8, 10.  
 
Collectively, these studies demonstrate patients with PAD have deficits in the muscular contribution of the 
ankle plantarflexors, which decrease propulsion during walking. Ankle plantarflexor torque and power in late 
stance is of great importance as it represents the greatest contribution to overall power during ambulation. The 
findings from these preliminary studies motivated the intervention to increase propulsion with an AFO.  
 
Supervised exercise therapy improves peak walking distances but not lower extremity torques and 
powers. Preliminary unpublished data from our laboratory was collected in 23 patients with PAD (Age: 60.3 ± 
7.21 years; Body Mass: 82.6 ± 18.05 kg) who completed a supervised walking program for six months. Joint 
torques and powers were calculated from subjects walking prior to the onset of claudication pain at baseline 
and after the exercise program. Of the 23 subjects collected, the ankle plantarflexor torques were unchanged 
or worsened (decreased torque) in 14 subjects following the exercise program (Figure 5). To examine whether 
patients with PAD were 
able to redistribute joint 
torque 
following 
the 
exercise program, we 
investigated 
hip 
extensor torque in early 
stance. 
Redistribution 
of torque is a strategy 
to use one joint to 
compensate for a deficit 
in 
another 
joint, 
to 
achieve 
propulsion 
during 
walking. 
However, 
instead 
of 
torque 
redistribution, 
we 
found 
similar 
decreases in the hip as the ankle, with 13 of the 23 patients having no change, or further decrease, in peak hip 
extensor torque following the exercise intervention (Figure 6). Regarding power, a total of 16 patients had 
unchanged or decreased ankle plantarflexor power (Figure 7), and 11 patients had unchanged or decreased 
hip extensor power after participating in supervised exercise for six months (Figure 8). Of note, all 23 subjects 
improved the peak walking distance 685 meters on average. Of subjects whose ankle plantarflexor torque did 
not improve, their peak walking distances were still increased an average of 669 meters. While it is a positive 
result that patients are increasing the maximum distance that they can walk after completing a six month 
exercise program, lack of improvement in gait biomechanics means there is untapped potential for further 
improvements in the walking performance of these individuals. 
Figure 5. Changes in 
ankle 
plantarflexor 
torque after completing a 
supervised 
exercise 
program in patients with 
PAD. Fourteen subjects 
had 
unchanged 
or 
decreased 
torque 
values, even though the 
maximum distance these 
patients could walk was 
increased, which shows 
that treadmill exercise 
does not improve the 
ability of muscles with 
myopathy 
to 
produce 
torque. 

 
 
 
 
 
 
Wearing an ankle foot orthosis immediately improves walking performance in patients with PAD. 
Four patients with PAD (Age: 66.0 ± 10.9 years; Body Mass: 84.3 ± 17.1 kg) completed pilot testing of initial 
and maximum claudication distances while walking with and without an AFO. Patients completed a 
progressive-load treadmill test67. During the treadmill test, the patients with PAD walked on a treadmill that 
started at 0% grade and 0.83m/sec. Every two minutes, the grade was increased by 2% up to a maximum of 
15% grade. The first indication of claudication pain was recorded as initial claudication distance, while the total 
distance the patients could walk on the treadmill before stopping because of pain was the absolute claudication 
distance67. Throughout the test, we asked the patient to confirm the presence or absence of pain to ensure the 
Figure 6. Changes in hip 
extensor torque following six 
months 
of 
a 
supervised 
exercise 
program 
demonstrate at least half of 
the 
patients 
have 
no 
improvement 
or 
further 
decreased values for torque. 
Unlike 
healthy 
older 
individuals, patients with PAD 
still do not redistribute torque 
from the ankle to the hip, but 
rather maintain an overall 
decreased 
torque 
profile 
d
ith h
lth
ld
Figure 7. Changes in ankle 
plantarflexor power of patients 
with PAD who completed a 
supervised exercise program. 
Sixteen 
subjects 
had 
unchanged 
or 
decreased 
ankle power generation, even 
though the maximum distance 
these patients could walk was 
increased, which shows that 
treadmill exercise does not 
improve the ability of muscles 
with myopathy to produce 
power at the end of the 
stance phase of walking. 
Figure 8. Eleven patients with 
PAD 
had 
unchanged 
or 
decreased hip extensor power 
following 
the 
supervised 
exercise 
program. 
These 
results 
demonstrate 
that 
patients with PAD do not 
improve ankle propulsion, or 
redistribute power to the hip 
even 
following 
supervised 
exercise. 
 

correct initial claudication distance was recorded. We counterbalanced the effect of the AFO by having two 
patients walk first with the AFO, while the other two walked first without the AFO to prevent a fatigue effect. On 
average, the patients’ initial claudication distance was 140.1 ± 72.5 meters while walking without the AFO and 
183.5 ± 121.2 meters while walking with the AFO (Figure 9). The average maximum claudication distance was 
366.0 ± 118.3 meters without the AFO and 492.3 ± 66.8 meters with the AFO (Figure 10). Thus, the four 
patients increased the maximum distanced walked by about 50 meters just by wearing the AFO. These 
increases in initial and maximum walking distances are comparable to those seen after pharmacotherapy for 
six months29, 32.  
Wearing an AFO trends 
towards 
redistribution 
of torque to the hip in 
patients with PAD. Four 
patients with PAD (Age: 
60.3 ± 7.21 years; Body 
Mass: 82.6 ± 18.05 kg) 
were tested while walking 
overground 
with 
and 
without the AFO. Peak 
torque was calculated for 
the ankle at the end of 
the stance phase and hip 
extensor 
torque 
was 
calculated 
from 
early 
stance in each condition. 
The preliminary results 
show that the ankle 
plantarflexor 
muscles 
have to contribute less 
torque to walking while 
wearing 
the 
AFO, 
as 
the 
ankle 
plantarflexor torque in these four subjects 
decreased while wearing the AFO (Figure 
11; 1.280 ± 0.14 Nm/kg without the AFO 
and 1.22 ± 0.12 Nm/kg with the AFO). 
This decrease in ankle plantarflexor 
torque while wearing the AFO was not 
expected, but surprisingly, the overall 
torque profile was also maintained. Thus, 
our results indicate that walking with the 
AFO helps patients with PAD in two ways: 
1) contributing mechanical torque during 
propulsion and 2) reducing the demands 
on the myopathic calf muscles of these 
patients. The hip extensor torque also 
increased with the AFO (Figure 12; 0.602 
± 0.12 Nm/kg without the AFO compared 
with 0.621 ± 0.12 Nm/kg with the AFO). 
While these increases are small, the fact that all four of the patients actually increased is significant 
considering that at least 50% of subjects decreased in these same variables following supervised exercise in 
our preliminary data presented earlier. This subset of preliminary data provides optimism as to the potential of 
the AFO to improve both walking distances and torque profiles in patients with PAD both acutely, and following 
a three month AFO intervention.  
Opportunity presented by an ankle foot orthosis (AFO) intervention: Recent studies in healthy and neurological 
populations have demonstrated that simple AFOs can increase walking performance through reduced energy 
expenditure26, 28, 68. While powered exoskeletons have been a hot-topic in media and pop-culture, clinicians and  
Figure 9. Initial claudication distances 
improve while walking with an ankle foot 
orthosis 
(AFO) 
compared 
to 
walking 
without an AFO in patients with PAD.  
Figure 
10. 
Maximum 
claudication 
distances are increased in patients with 
peripheral arterial disease when walking 
with an ankle foot orthosis (AFO). 
Figure 11. The required torque contribution of the ankle 
plantarflexors was decreased in four patients with PAD when 
wearing the AFO. Thus, the AFO contributes mechanical force in 
place of the ankle plantarflexors and also decreases the oxygen 
demand by requiring less exertion from those muscles. 

scientists 
are 
appropriately 
cautious 
realizing 
that 
such 
technology is far 
from being practical 
and affordable for 
all individuals who 
would 
benefit. 
However, an off-
the-shelf AFO is 
the least complex 
form 
of 
exoskeleton, that is 
easily adjustable, affordable, and 
available 
to 
immediately 
be 
prescribed and worn by patients 
with PAD wishing to walk further 
who do not wish or are not 
candidates 
to 
undergo 
an 
operation.  
 
Research Plan 
Study Design: We plan to 
recruit 50 patients with PAD from 
the claudication clinic at the 
Nebraska and Western Iowa 
Veterans Affairs’ Medical Center 
(VAMC) in Omaha, Nebraska 
(Figure 
13). 
As 
we 
just 
completed enrollment of a five-
year NIH grant that included 200 
patients (R01 AG034995) and 
have collected over 50 patients 
in 18 months for a COBRE 
research 
project 
(P20 
GM109090), 
we 
expect 
this 
recruitment goal to be attainable. 
The 
collaborating 
vascular 
surgeons, Drs. Johanning and 
Pipinos, will evaluate all patients 
seen 
at 
the 
University 
of 
Nebraska Medical Center and 
Veterans’ Affairs Medical Center 
claudication clinics. The PI also 
participates in these clinics and 
works side by side with the 
surgeons. 
Inclusion criteria: At entry into 
the study, all subjects must: 
1) be able to give written, 
informed consent 
2) demonstrate 
positive 
history of chronic claudication 
3) demonstrate 
exercise-
limiting claudication established 
by history and direct observation 
Figure 12. Wearing the 
AFO allowed four pilot 
subjects to increase hip 
extensor 
torque 
during 
early 
stance, 
which 
is 
consistent 
with 
the 
redistribution 
of 
torque 
from the ankle to the hip 
seen 
in 
healthy 
older 
individuals. Utilizing the hip 
muscles 
would 
further 
decrease the demand on 
the 
ankle 
plantarflexors 
while walking with an AFO. 
Figure 13. Study 
Design 
 

during a screening walking test administered by the evaluating vascular surgeon.  
4) have an ankle/brachial index < 0.90 at rest69  
5) and have a stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor 
control for 6 weeks. 
Exclusion criteria: Any potential subjects will be excluded if they have: 
1) rest pain or tissue loss due to PAD (Fontaine stage III and IV)69 
2) acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma 
3) walking capacity limited by conditions other than claudication including leg (joint/musculoskeletal,  
neurologic) and systemic (heart, lung disease) pathology 
 
Specific Aim 1: Determine the acute impact of the AFO on walking performance  
Approach: We propose to study 50 patients with PAD, measuring walking performance with and without 
wearing a carbon composite AFO. Patients will wear the AFO on the affected leg(s), so patients with bilateral 
leg symptoms will wear them on both legs while patients with unilateral disease will wear the AFO on the 
symptomatic leg only. Walking performance will include measurement of initial and absolute walking distances, 
and lower extremity torque and power. Energy cost and muscle activity will be tested as potential mechanisms 
contributing to improvement in walking performance. Conditions will be randomized, with half of the subjects 
performing the tests without the AFO and the other half starting with the AFO walking conditions. All data will 
be collected in the Biomechanics Research Building (BRB). All subjects will be consented after reporting to the 
BRB and the outcomes detailed below will be assessed. The entire process is expected to take 2.5 hours. 
Outcomes 
1) Initial and absolute walking distances: Walking distances will be determined with a progressive-load 
treadmill test67 with initial and maximum claudication distances as outcomes. During the treadmill test, 
patients with walk on a treadmill that starts at 0% grade and 2.0 mph. Every two minutes, the grade will 
be increase by 2% up to a maximum of 15% grade, and the speed held constant throughout the test67. 
2) Lower extremity torque and power: Biomechanical data will be collected using eight in-ground AMTI 
force platforms and a 12 camera high speed digital motion capture system (Cortex 5.1, Motion Analysis 
Corp, Santa Rosa, CA) to collect three dimensional kinematics (60 Hz) and kinetics (ground reaction 
forces, 600 Hz). Reflective markers will be placed at specific anatomical locations on the lower limbs, 
utilizing the marker systems of Vaughan70 and Nigg71. Following the setup, kinematics and ground 
reaction forces will be recorded while the subjects walk with their self-selected pace through a ten-
meter pathway. Each patient will be tested before the onset of claudication pain (pain free) with a 
mandatory one-minute rest period between the walking trials to insure that all trials are in a pain free 
condition. A total of five walking trials per leg will be collected. Following the collection of overground 
data, the patients with PAD will be allowed to rest.  
 
Data are exported and processed in custom laboratory software using MATLAB (Mathworks Inc., MA) 
and Visual 3D (C-Motion, Inc., MD). This software is used to calculate ground reaction forces for the 
vertical, anterior-posterior, and medial-lateral direction, and joint angles and joint angular velocity for 
the hip, knee, and ankle during the stance phase of walking. Lower extremity joint muscular responses 
and contributions during walking are determined using joint torques and powers. Joint torques and 
powers are calculated using inverse dynamics for the hip, knee, and ankle during the stance phase of 
walking. Inverse dynamics combine the kinematics and the ground reaction forces as described by 
Winter72. Additionally, spatial and temporal characteristics will be calculated using custom code in 
MATLAB (Mathworks Inc., MA). From this data our primary lower extremity function outcome measures 
will be ankle and hip plantarflexor torque and power, although all kinematic and kinetic measures of the 
lower extremity will be investigated. 
3) Muscle activity: Electromyographic data will collected from the gasctrocnemius and soleus muscles of 
the affected legs at 1000 Hz using surface electrodes with the DelSys Trigno™ wireless system. Prior 
to the trials maximum voluntary contraction electromyographic signals will be recorded for each muscle 
via isometric contraction for three seconds. For electromyographic data analysis, time-domain and 
frequency-domain analyses will be performed using custom Matlab programs. Time-domain analysis of 
electromyographic signal provides a measure of the average muscle activity and work produced by a 
given muscle (activation profiles) 73. The mean electromyographic signal (EMGmean) will be computed to 
measure the average muscle activity for each trial. The electromyographic envelope (EMGenv) will also 
be calculated by integrating the time series of root-mean-square electromyographic signal for each trial. 
EMGenv provides a measure of the muscle work for a given trial. Frequency-domain analysis of 

electromyographic signal provides a window into muscle fatigue and motor unit recruitment 73. The raw 
electromyographic signal will be converted to the frequency domain using a Fast Fourier Transform to 
determine the power spectrum. Median frequency and frequency bandwidth will be computed from the 
power spectrum. Median frequency will be computed as the frequency at half of the integrated power 
spectrum as given by the following equation (1) 73: 
 
  
where P(f) is the power at frequency f, fmed is the median frequency, and fmax is the maximum frequency 
of the power spectrum. Frequency bandwidth (fband) is the difference between the highest and lowest 
frequency where the power exceeds half the maximum power of the power spectrum.  
 
4) Energy cost: A portable metabolic cart (Cosmed K4b2, Cosmed USA Inc., Chicago, IL), will be used to 
measure gas exchange on a breath-by-breath basis, providing a measure of oxygen consumption. 
Steady-state oxygen consumption in ml/kg/min will be calculated during the walking distance test.  
 
Statistical analysis: The sample size was calculated to detect effect sizes observed in pilot data for initial and 
absolute walking distances. The mean (SD) difference in initial walking distance with and without AFO was 
43.4 meters (93), corresponding to a standardized effect size of 0.47 standard deviations. A sample size of 50 
subjects will provide 84% power to detect differences of 0.47 standard deviations between walking with and 
without an AFO, using a paired t-test for sample size estimation purposes only, and a significance level of 0.02 
to informally adjust for multiple testing. The standardized effect size for absolute walking distance was 1.29 
standard deviations, so the sample size of 50 subjects will also provide sufficient power to detect this 
difference. For statistical analysis, a linear (or generalized linear, as appropriate) mixed modeling approach will 
be used. This approach will allow us to detect differences between walking with and without an AFO while 
adjusting for confounding variables. The level of significance will be set at 0.05. 
 
Expected results/possible limitations: Based on work with AFO devices in other pathological populations, 
we expect the AFO will improve lower extremity torque and power generation enough to demonstrate a 
clinically important difference. If our hypothesis is correct, the AFO will be a potential new conservative 
intervention for improving walking performance in patients with PAD, along with the mechanisms contributing 
to those improvements. If our hypothesis is not supported, we speculate that the AFO may still be a viable 
conservative treatment option based on results of Specific Aim 2. For example, the AFO may improve walking 
performance over the course of the three-month intervention. This aim will also provide data on muscle 
contribution that could be used to design and test an improved AFO.  Our preliminary work looks promising for 
increasing the distance that patients with PAD can walk. Completion of this aim will provide the groundwork for 
exploring and designing even more effective AFO devices. 
 
Specific Aim 2: Determine improvements in walking performance following a three month AFO intervention 
Approach: We propose to study a subset of 30 patients from Specific Aim 1 measuring walking performance, 
physical activity, and quality of life after a three-month AFO intervention. Walking performance will be 
assessed in the same manner as in Specific Aim 1 during the baseline assessment. Physical activity will be 
assessed using accelerometers while quality of life will be assessed through questionnaires. To investigate 
mechanisms contributing to improvements in walking performance, physical activity and quality of life, we will 
measure changes in energy cost, muscle morphometric parameters, muscle oxygenation, and muscle strength 
and endurance at baseline and following each of the three month intervention arms (control and AFO).  
 
AFO and Control Intervention: Patients will be asked to wear an AFO each day for three months. Subjects 
will have an off-the-shelf AFO (Figure 2) chosen initially based on shoe size and adjusted or exchanged for a 
different size during the initial evaluation after entering the study. The patients will be asked to wear the AFO at 
all times except when they are in bed or showering/bathing. The instructions given to the patients about 
walking will be the same as typically provided by clinicians, which is to walk 30 minutes per day, most 
days/week. We have chosen this specific AFO device because it is already available for use in a clinical 
environment, is composed of a carbon-composite material that will capture and return energy during the gait 
cycle, and has successfully contributed to propulsion during walking in other clinical populations26, 28. Patients 
will be able to contact the nurse coordinator at any time if they need the AFO adjusted or have questions about 
what should happen during the intervention. Subjects in the control arm will be asked to continue the same 
lifestyle for three months. The intervention arm order will be randomized (see Statistical Analysis) 



max
)
(
)
(
0
f
f
f
med
med
df
f
P
df
f
P



max
)
(
)
(
0
f
f
f
med
med
df
f
P
df
f
P
(1) 

Outcomes: All outcomes will be assessed at baseline and following each arm (control and AFO). 
1) Initial and absolute walking distances, 2) Lower extremity torque and power, 3) Muscle activity, 
and 4) Energy cost will all be measured as described for Specific Aim 1. 
5) Physical Activity: Participants will wear the Actigraph (Actigraph GT3X, Actigraph, FL, USA) 
accelerometer on their hip for seven days (the whole day except when sleeping) prior to starting the 
AFO intervention to measure baseline activity level. The accelerometer will be mailed back to 
researchers in a pre-paid envelope. Two weeks prior to the post-intervention visit to the laboratory, an 
accelerometer will be mailed to participants to wear the final seven days before the visit. Average 
steps/day, maximum cadence, and average peak activity index will be calculated.  
6) Quality of Life: The Walking Impairment Questionnaire74, Medical Outcomes Short Form 36, and 
Edinburgh Claudication Questionnaire will be used to assess quality of life. The Walking Impairment 
Questionnaire has been validated in patients with claudication74 and the Short Form 36 has been 
extensively evaluated and tested with a variety of populations and is able to distinguish between groups 
of varying health status75, 76. The Edinburgh Claudication Questionnaire was developed in an iterative, 
systematic fashion and has been implemented as a more holistic approach to identify presence of 
intermittent claudication in many clinical trials.20, 77-82 
7) Morphometric parameters: An ultrasound transducer (LS128 CEXT-1Z, Telemed, LT, Lithuania) will 
be used to assess thickness of the plantarflexor muscles using a standard real time B-mode image. 
Muscle thickness will be measured on the posterior medial and lateral surfaces, 20, 30, and 40% 
between the lateral malleolus of fibula and the lateral condyle of the tibia. The average values of 
muscle thickness at all measured sites will be the primary outcome measure. 
8) Muscle Oxygenation: Continuous-wave near infrared spectroscopy (Moxy Monitor, Fortiori Design 
LLC, MN, USA) will be measured bilaterally on the gastrocnemius calf muscle before, during and after 
the walking distance test. We will measure resting StO2, minimum StO2 during the maximal treadmill 
test, time to minimum StO2, and the StO2 recovery time. 
9) Muscle Strength and Endurance: An isokinetic dynamometer (Biodex 4 Medical Systems, Inc. USA) 
will be used to measure peak isokinetic strength (torque) of the ankle and hip of the more symptomatic 
leg. Peak torque and total work performed for ankle plantarflexion, ankle dorsiflexion, hip flexion, and 
hip extension will be measured. Subjects will perform one trial of five repetitions at 60 degrees/second 
to assess strength, and one trial of 15 repetitions at 120 degrees/second to assess endurance.  
 
Statistical analysis: A portion of patients from Aim 1 will be randomized to one of two intervention arms 
(control then AFO, or AFO then control). We expect differences from a 3-month training to be larger than the 
immediate differences shown in Aim 1. A sample size of 30 subjects (15 per treatment arm) will provide 80% 
power to detect differences of 0.59 standard deviations between walking with and without an AFO, using a 
paired t-test for sample size estimation purposes only, and a significance level of 0.025 to adjust for multiple 
testing. This sample size will also allow us to detect an effect size of 1.2 for differences between the two 
groups at each time point. Assuming a 10% drop-out rate, we will randomize 17 per group, for a total of 34 
subjects. For statistical analysis, a linear mixed modeling approach (or generalized linear mixed model, as 
appropriate) will be used. This approach will allow us to detect differences within and between groups, and 
adjust for confounding variables. The main comparison of interest will be changes in walking distances due to 
wearing the AFO. The use of the crossover design will allow us to investigate several questions of interest: 1) If 
walking distances improve after wearing the AFO for 3-months; 2) If walking distances worsen over the first 3 
months for subjects not wearing the AFO in the first period; and 3) If the improvement in walking distances 
from wearing the AFO for three months is retained over the second 3 months (no AFO).  To evaluate the 
relationship between improvements in walking performance, physical activity, and quality of life, and 
improvements in morphometric parameters, muscle oxygenation, and muscle strength and endurance, multiple 
correlations will be used. The level of significance will be set at p=0.05. 
 
Expected results/possible limitations: We hypothesize that an AFO intervention will increase walking 
performance, physical activity levels, and quality of life through improvements in the function of the muscles of 
the treated legs. If our hypothesis is correct, the AFO intervention is a new effective conservative intervention 
for patients with PAD. Because the premise is that the AFO will maintain overall torque and power while 
requiring a lower contribution from the leg muscles of patients, the patients will be able to walk further, placing 
less stress on their leg muscles, thereby allowing regeneration of structure and function of the muscles. 
Another possibility is that the patients experience an improvement in their walking performance, physical 
activity levels and quality of life but do not see improvements in muscular function of the legs. In this case, the 

AFO would still be beneficial for patients to use. However, if none of the components of our hypothesis are 
correct, and neither the function and quality of life nor the muscle characteristics improve despite conscientious 
use of the AFO, then our study would direct us away from AFO-type treatments and towards other therapies 
and rehabilitation geared towards muscle health. 
 
Specific Aim 3: Determine the feasibility of a three month AFO intervention 
Approach: We will utilize Bowen and colleagues’ standards for feasibility studies to measure the feasibility of 
using an AFO over three months in a random subset of 20 patients from Specific Aim 2. We will employ 
interviews and surveys throughout the three-month AFO intervention period to assess the following outcomes.  
Outcomes 
1) Acceptability: Interviews and a satisfaction survey will be implemented to assess satisfaction of using 
an AFO, intent to continue use, and perceived appropriateness measured. The research team will 
conduct interviews at 1.5 months, and three months. Interviews will last no longer than 30 minutes and 
will take place at the UNO Biomechanics Research Building. Satisfaction surveys for all participants will 
be completed during the final assessment in the Biomechanics Research Building.  
2) Demand:  Actual use and perceived demand will be measured using an accelerometer and interviews. 
An additional accelerometer will be given to the patient at the baseline visit. Battery life on these 
accelerometers can span over 30 days, especially with a lower sampling frequency of 1 Hz. Each 
month a new accelerometer will be mailed to participants and the package will include a pre-paid mailer 
for subjects to return the previous accelerometer for downloading data and charging. Additionally, 
patients will be contacted randomly three times during the 3-month study period to further assess the 
actual use. Perceived demand will be assessed via interview at baseline and at three months. 
3) Implementation: Degree of use, success/failure of use, and factors affecting the ease/difficulty of use 
will be measured using interviews to determine implementation. Interviews will take no longer than 30 
minutes and will occur at 1.5 months and 3-month time points.  
4) Practicality: Measurements of the positive/negative effects of the AFO and ability of participants to 
effectively use the AFO will be made to determine the practicality of the intervention. We will assess 
these factors via interviews at three months. 
 
Analysis for Specific Aim 3, Outcomes 1-4: Data from interviews will be transcribed and analyzed by the 
research team in NVivo 10 (QSR International Pty Lid., Victoria, AU). Researchers will independently code 
transcripts and meet to reach agreement on major data themes. Emerging themes will be identified using a 
constant comparison approach. This approach allows for the development of explanations through patterns 
but also allows the coder to harness theory and prior knowledge or research to answer research questions. 
 
Statistical analysis: Descriptive statistics will be used to summarize results of survey data. We will use counts 
and percents for categorical data, and means and standard deviations for quantitative data. Associations 
between walking distance variables and acceptability, use, and practicality variables will be examined using t-
tests for dichotomous variables and correlations for continuous variables. 
 
Expected results/possible limitations: We expect that an AFO intervention will be feasible to implement for 
three months in patients with PAD. If our hypothesis is correct, the study will establish the AFO as a new 
intervention that will likely be easily adopted by patients. It is also possible that the intervention does not prove 
feasible in one or more areas. If that happens, the study results will provide specific information on which 
aspects of the application of AFO treatment are not feasible. Those area(s) can then be further evaluated and 
potentially improved. Importantly, the results will inform the importance of these areas to feasibility of all 
interventions for the PAD patient group, not just the AFO intervention proposed in the current study. 
 
Table 2: Project Timeline 
1st Year 
2nd Year 
3rd Year 
4th Year  
5th Year 
Subject recruitment 
XXXXXX 
XXXXXX 
XXXXXX 
XXXXXX 
XXX 
Baseline assessment 
    XXXX 
XXXXXX 
XXXXXX 
XXXXXX 
 
AFO and Control Intervention Arms 
    XXX 
XXXXXX 
XXXXXX 
XXXXXX 
XXX 
Post AFO and Control assessments 
      XX 
XXXXXX 
XXXXXX 
XXX 
XXX 
Data analysis 
 
XXXXXX 
XXXXXX 
XXXXXX 
XXXXXX 
Abstract/manuscript development 
 
       XXX 
XXXXXX 
XXXXXX 
XXXXXX 
Grant writing 
 
 
 
XXXXXX 
XXXXXX 
 

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