RFA-AG-16-013Development of Measures of Fatigability

in Older Adults (R21)

National Institute of AgingNational Cancer Institute

Pre-Application WebinarJuly 23, 20152:00 pm EDT

Basil Eldadah, MD, PhD (NIA) Sandra Mitchell, CRNP, PhD, AOCN (NCI)

Ashley Wilder-Smith, PhD, MPH (NCI)

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• Introductions• Overview of the RFA

– Background and rationale– Description of the funding opportunity– Responsiveness– Application mechanics

• Questions

Agenda

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A subjective lack of physical and/or mental energy that is perceived by the individual or their caregiver to be interfering with a person’s usual or desired activities

Reference: Multiple sclerosis council for clinical practice guidelines. Fatigue and multiple sclerosis: Evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America, 1998.

Fatigue Definition

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References:

1) Hardy et al. Journal of the American Geriatrics Society 2008; 56:1910-1914.

2) Gill et al. Annals of Internal Medicine 2000; 135:313-321.

• In older Medicare or VA primary care clinical patients, feeling tired most of the time predicted mortality independent of a variety of covariates including age, morbidities, and function (1)

• Among older community-dwelling adults who were previously non-disabled, self-reported fatigue, low energy or tiredness was the most common reason for restricting activity (2)

Fatigue in Older Adults

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• Significant health concern and a disabling symptom experienced by 90% of patients during and following cancer treatment

• Limited progress in delineating the etiology and pathophysiology of fatigue in cancer

• Fatigue treatments (e.g., exercise, mindfulness-based stress reduction) [1] are: – non-specifically applied to a vaguely defined symptom– treatment responses have been difficult to capture

• Fatigability measurement in cancer may contribute to: – identifying distinct domains of fatigue– distinguish fatigue from related phenomenon such as depression,

diminished cardiopulmonary reserve, or asthenia

Reference: Mitchell SA et al.(2014). Putting Evidence into Practice (PEP): A 2014 update of evidence-based interventions for cancer-related fatigue during and following treatment. Clinical Journal of Oncology Nursing, 18 (6), 38-58.

Fatigue in Cancer

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• Mainstay of CRF measurement has been self-report

• Fatigue measures capture individual perceptions (severity, distress, interference or bother) of the sensation of fatigue

• Neglect the important context of physical and functional performance demands in daily life

• Activity level provides important context for self-report of fatigue

Why Activity Context Matters

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• Consider two 64 year-old individuals receiving chemoradiotherapy for rectal cancer

• Both report severe fatigue on a validated self-report scale, yet the physical and functional performance demands of their daily lives are markedly different: • One individual continues full-time employment, walks 4 miles daily,

and lives in a two-story house• The other is retired, lives in a small apartment adjoining the home of

a family member, and prefers quiet and sedentary activities• Self-reported fatigue levels are similar, however the intensity and duration

of activity that provokes fatigue, that is fatigability, would likely differ substantially.

• Isolated measurement of fatigue perception provides incomplete information to distinguish and treat these individuals

• Measurement of daily activity alone cannot disentangle lifestyle choices or behavioral changes that result from self-pacing or functional impairment

Case Example

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Reference: Junghaenel et al. Journal of Psychosomatic Research 2011;71:117-123

• Most commonly used measures of fatigue including PROMIS Fatigue, FACIT-Fatigue and Vitality subscale of the SF-36 provide approximately comparable estimates of fatigue in adults ages 29 to 75

Comparison of Fatigue Instruments

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• Fatigability is related to, but distinct from, fatigue, with different requirements for

measurement

• Captures the ratio of perceived fatigue or decline in performance relative to a defined

physical activity of a specific intensity and duration (demand)– Examples of demand may include walking, climbing stairs, carrying groceries, exercising

• Provides complementary and non-overlapping information to self-reports of fatigue

perception

• Offers a potentially less biased, more objective approach to measuring the degree to

which fatigue limits someone physically, and may provide a more precise measure of

clinically significant fatigue

Perceived Fatigability• An individual’s self-reported feeling of fatigue as a function of the duration and

intensity of a demand task or activity.

Performance Fatigability• Decline in force, endurance, power, speed, reactivity, or accuracy of performance

of a given activity or task.

Definition of Fatigability

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Fatigability may be measured by a performance decrement in the context of a standardized demand.

Slope of the decline in performance may vary within and between individuals

Fatigability: Decline in Performance in the Context of a Standardized Demand

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Fatigability can also be captured as the ratio between self-report of fatigue during or following an activity with a standardized demand.

Fatigability: Ratio between Self-Report of Fatigue and a Standardized Demand

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• Perceived fatigability: Self-reported fatigue and demand assessed by separate instruments

• Patient-reported outcomes (PROs) can be used to measure both the self-reported magnitude of fatigue and the duration and intensity of physical or cognitive demand that induces fatigue

• Self-reports of fatigue magnitude and demand should be gathered in close temporal proximity.

• Multiple PRO measures of fatigue are available, ranging from a one-item visual analog scale or rating of perceived exertion to multi-item and multi-dimensional inventories

Examples of Potential Fatigability Measurement Approaches (1 of 5)

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• PRO measures of demand have also been proposed, such as the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire, the Paffenbarger Physical Activity Questionnaire, or other instruments that may or may not convert responses into metabolic equivalents (METs)

• Advantages and Disadvantages: • Use of PROs to measure the magnitude of fatigue and the

duration/intensity of demand allows for situation-specific measures of fatigability

• Fatigability measures that rely solely on PROs are feasible in survey research settings and lower resource clinical settings

• Reliance on PRO measures may pose threats to validity and interpretation, including recall, social desirability, and response shift biases

Examples of Potential Fatigability Measurement Approaches (1 of 5 continued)

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• Perceived fatigability: Self-reported fatigue and demand assessed by a single instrument

• Both the magnitude of fatigue and the duration and intensity of physical or cognitive demand that induces that fatigue are measured by self-report in a single instrument.

• Examples of PROs with varying levels of specificity for demand parameters have been published [1-3]

• Both self-reported fatigue and demand are assessed in the same question

• Questions solicit the recalled level of fatigue experienced during or after various demands of specified nature, duration, and intensity

1 Glynn et al., J Am Geriatr Soc, 2015. 63(1): p. 130-5.2 Tiesinga et al., Int J Nurs Stud, 1998. 35(1-2): p. 115-23.3 Yang and Wu, Qual Life Res, 2005. 14(5): p. 1357-62.

Examples of Potential Fatigability Measurement Approaches (2 of 5)

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• Strengths and Limitations:• Potential to probe across a variety of demand types,

allowing for situation-specific measures of fatigability

• May be feasible in survey research settings and lower resource clinical settings

• Recall, social desirability, and response shift biases pose threats to validity and interpretation

• Limitations in the specificity with which demand parameters are described may lead to variability in respondents’ interpretations of the envisioned or recalled effort required for each demand

Examples of Potential Fatigability Measurement Approaches (2 of 5 continued)

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• Perceived Fatigability: Self-reported fatigue combined with objectively measured demand

• Magnitude of fatigue is measured by self-report while physical or cognitive demand associated with that fatigue is quantified through objective measures

• Examples of this approach have been published [1-3]

• Fatigue is assessed using a PRO

• Demand is assessed in laboratory or free-living setting, using one of several possible measures (eg. actigraphy, oxygen consumption rate, standardized exercise, and other measures

1 Murphy and Smith, J Gerontol A Biol Sci Med Sci, 2010. 65(2): p. 184-9.2 Schnelle et al., J Am Geriatr Soc, 2012. 60(8): p. 1527-33.3 Simonsick et al., J Am Geriatr Soc, 2014. 62(2): p. 347-51.

Examples of Potential Fatigability Measurement Approaches (3 of 5)

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• Strengths and Limitations: • Ecological validity of fatigue measurement may be

strengthened by repeated dynamic PRO sampling of fatigue experience, such as through ecological momentary assessment

• Observer effects pose threat to validity of activity measurement

• Optimal epoch length and sampling frame for energy expenditure estimates derived from actigraphy need to be

determined

Examples of Potential Fatigability Measurement Approaches (3 of 5 continued)

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• Performance fatigability: Fatiguing task followed by probe task

• Fatigability is operationalized as a decrement in performance due to tiredness on a probe task after engaging in a separate high-intensity or prolonged standardized physical or cognitive task meant to induce fatigue (demand)

• Assessment of fatigue is reflected by a decrement in force, endurance, power, speed, reactivity, or accuracy on a probe task relative to a reference value or prior baseline (for example using the 6-minute walk, maximal grip strength, stair climb, standard Stroop Test, Trail Making A & B Test, Digit Symbol Substitution Test)

Examples of Potential Fatigability Measurement Approaches (4 of 5)

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• Assessment of demand is reflected by maximal or sub-maximal exertional tasks• Examples include graded cycle ergometry, graded treadmill walking, or

cognitive exertional tasks such as the prolonged Stroop Test, prolonged Trail Making A & B Test, and the prolonged Digit Symbol Substitution Test

• Strengths and Limitations:• Standardized parameters for the performance of specific usual or daily

activities, particularly with regard to intensity, are needed for inter-individual comparisons

• Minimally important decrement from standard or prior baseline needs to be identified

• Observer effects may compromise the validity of fatigue and activity measurements; diminished performance may be misattributed to pain,

breathlessness, or other activity-limiting symptoms

Examples of Potential Fatigability Measurement Approaches (4 of 5 continued)

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• Demand tasks may be• standardized daily-living physical activities (e.g. vacuuming

for 10 minutes, carrying 10 pounds of groceries up 5 stairs)

• sub-maximal or maximal physical exertional tasks (e.g. graded cycle ergometry, treadmill walking)

• daily-living cognitive activities (e.g. reading a paragraph and answering questions about the content)

• exertional cognitive tasks (e.g. prolonged Stroop Test, prolonged Trail Making A & B Test)

Examples of Potential Fatigability Measurement Approaches (5 of 5)

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• Strengths and Limitations:• To permit inter-individual comparisons, standardized

parameters of the performance intensity of specific usual or daily activities are needed

• Minimally important decrement from standard or prior baseline needs to be identified

• Observer effects may compromise the validity of fatigue and activity measurements

• Diminished performance may be misattributed to pain, breathlessness, or other activity-limiting symptoms

Examples of Potential Fatigability Measurement Approaches (5 of 5 continued)

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• Valid and responsive measure of fatigability would advance knowledge of:– causal pathways by which fatigue affects

physical performance and functional status– better distinguish cancer-related fatigue

phenotypes [1]– mechanism-targeted interventions for fatigue

Reference: Piper BF, Cella D. Cancer-related fatigue: definitions and clinical subtypes. J Natl Compr Canc Netw. Aug 2010;8(8):958-966.

Understanding Fatigability

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• Mechanisms of fatigue • Population-based surveillance research• Stratification factor/eligibility criterion for trials of

supportive care and rehabilitation for fatigue • Endpoint reflecting therapeutic response to

treatments for fatigue• Assessment tool for clinical practice

Fatigability Measures: Envisioned Uses in Research and Clinical Practice

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• Establishmento Development of protocols varying distance, time walked, pacing

• Reliability and validation testingo Intra- and inter-rater reliabilityo Association with a variety of adverse outcomes; e.g., disability,

hospitalization, mortality• Interpretation

o Determination of threshold levels and minimal clinically important difference

• Implementation in practice (current and future efforts)o Use for screening for disability and underlying diseaseo Track progression of health statuso Define cut-points to inform clinical management decisionso Incorporate into work flow and electronic medical record

Development of a Clinical ToolGait speed as a case example

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• Development of a conceptual model of fatigability through systematic literature reviews; convening of focus groups comprised of patients, clinicians, content experts, and other relevant contributors and stakeholders; concept analyses; and other activities necessary to lay a solid conceptual groundwork.

• Reliability testing• Testing construct, content, and criterion validity.

Comparison with established functional measures is particularly important.

Examples of Potential Studies(non-exhaustive list)

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• Testing for measurement invariance across age, gender, race/ethnicity, and distinct levels of cardiopulmonary fitness or functional capacity.

• Demonstration of feasibility, responsiveness to change, and minimum clinically detectable change.

• Validation in specific populations of individuals; e.g., older adults, patients with cancer, cancer survivors, and persons with multiple chronic conditions (MCCs). Studies should consider the potential for factors such as pain, cachexia, sarcopenia, and other related conditions to confound measurement in these populations.

Examples of Potential Studies(non-exhaustive list, continued)

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The following activities are especially important: – Characterization of factors that influence how subjects arrive at

their self-reported evaluations of fatigability; e.g.:• time horizon• choice of comparator• prominence of past experiences• other response heuristics

– Development and refinement of language to ensure• readability• appropriateness of content to life stage and functional capacity (e.g.,

to avoid floor/ceiling effects)• consistency of meaning• appropriateness of stems• other item characteristics

Studies Involving PROs

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– Optimization of readability versus accuracy • Intensity, duration, or other characteristics of

activities should be worded in sufficient detail to permit adequate inter-individual comparisons.

• Applicants should conduct studies to determine the optimal balance between feasibility of the instrument for the settings in which it is intended, and its reliability in those settings.

– Adjustment for confounding by mood disturbances, impaired sleep, and pain

Studies Involving PROs (continued)

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• Applications will be reviewed administratively and assessed for responsiveness

• Evaluations of responsiveness will include the following considerations:– Applications that operationalize fatigability at the level of muscle

fibers, single muscles, or muscle groups will be considered non-responsive (e.g., repeated hand or foot contractions). This FOA is intended to support studies on fatigability at the level of the individual (“whole person” level).

– Applications that conceptualize fatigability as a symptom will be considered non-responsive. Fatigability in this FOA is an inherent attribute or characteristic of an individual, not a symptom.

Responsiveness

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• Purpose– Share information about awardees’ respective scientific

approaches– Discuss challenges encountered in measure development

activities– Explore opportunities for collaboration

• Logistics– Toward the end of each award year– In Bethesda, Maryland– No budget line item (modular budget), but explain in budget

justification

Grantee Meetings

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• Receipt date: October 1, 2015, by 5:00pm local time of applicant organization

• Review by special emphasis panel in January/February, 2016

• Council review in May, 2016• Earliest funding in July, 2016

– Set-aside funds

Application Mechanics