Rare Diseases and PROMIS: Opportunities
Natcher Conference Center
March 1, 2013
James Witter MD, PhD FACR
CSO PROMIS
Medical Officer: Rheumatic Diseases
NIH/NIAMS/DSRD
Dynamic Tools to Measure Health Outcomes from the Patient Perspective
Goals of presentation
• General Overview
• The ‘science’ of PROMIS
– Domain theory of disease
– Item Response Theory (IRT)
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title Adaptive
style Testing
• Application
Computerized
(CAT)
– Terminology
• Future in rare diseases
Definitions-Terminology
• Items are questions that have:
• Context, stems, responses
• Parameters (Difficulty, Discrimination)
– Important for analyses, calibration
• Banks (collection of items)
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• “calibrated” on a common metric
– difficulty and discrimination have been estimated
• Define common concept-domain
– Allow computerized adaptive testing (CAT)
• Domains
• Define latent traits/abilities
Item Response Theory
• In psychometrics- body of theory that:
• Describes application of mathematical models to
how people respond to items
» At person and item level
• Serves as basis for measuring
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» Abilities
» Attitudes
• Based on probability of endorsing a particular item
category is function of latent trait or ability
• Ability to improve reliability of instrument
IRT models Latent Traits:
People and Items are Represented on the Same Scale
Item Difficulty
Are you
able to
get out of
bed.
Are you able to
run 5 miles
Low
High
Low
High
Persons’ Levels of Physical Functi
5
DOMAINS
A domain is the specific feeling,
function, or perception you
want to measure.
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Cuts across different diseases
Evolving concept of health
DOMAIN
vs. title style
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DISEASE SPECIFIC
Domains & Diseases: Hypotheses
• Rare diseases are combinations of
different domains
– fatigue, physical function, anxiety, pain…
• Capturing multiple domains may be
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optimal
way
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assesstitle
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diseases
• Core-common PRO domains are
universally applicable across diseases,
ages and ethnicities
• Core PRO domains can link common and
rare diseases
Outcomes (FDA workshop & ICOAWG)
• Clinical Outcomes Assessments (COAs)
• PROs: Patient-reported outcomes
• ClinROs: Clinician-reported outcomes
• ObsROs: Observer-reported outcomes
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• all influenced
humanMaster
choices, judgment,
cooperation or
motivation
• Biomarkers
• not influenced by humans
Patient-Reported Outcomes (PROs)
• FDA and NIH recognize PROs as
important outcomes to answer clinical
questions
– translating the efficacy-effectiveness and
safety to
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therapeutics
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• In development (clinical research)
• In the real world (clinical care)
• Patient burden is important aspect of PRO
assessment in both these settings
The Tower of Babel (Brueghel, 1563)
Advancing Patient-Centered Outcomes
PROMIS: A Common Source of PROs
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Clinical Practice
Surveys (CDC)
Clinical research
Clinic
Hospital
NIH
Industry
FDA
NIH PROMIS
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PROMIS: Present
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PROMIS Resources
Informatics
Assessment Center
Supports >100 Studies
Advancing Knowledge
>100 Peer-Reviewed
Publications
Cooperative Group
12 Research Sites
3 Centers
150+ Scientists
Tools
40 Adult Measures
20 Pediatric Measures
Translations
All item banks  Spanish
DOMAINS
Common DOMAINS
• Fibromyalgia
• Pain, fatigue, depression
• SLE
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• Fatigue, pain, social function
• RA
• Pain, physical function, fatigue
Mechanisms
PROs
Interleukins
Phys Fn
Fatigue
Chemokines
Prostaglandins
Social
Sleep
Anxiety
Pain
Fatigue Item Bank
Lower Back
Pain
Depression
Heart Failure
Cancer
COPD
Same metric, same meaning
PROMIS Measures Tested in Six Conditions
Condition
Relevant Item Banks
COPD
Physical Function
Fatigue
Pain
Social Role Satisfaction
Emotional Distress (Depression, Anxiety, Anger)
Heart Failure
Physical Function
Fatigue
Social Role Satisfaction
Depression
Low Back Pain
Pain (Interference and Behavior)
Physical Function
Depression
Fatigue
Sleep Disturbance
Depression
Emotional Distress (Depression, Anxiety, Anger)
Sleep Disturbance
Fatigue
Physical Function
Pain
Arthritis
Physical Function
Cancer
Pain
Fatigue
Emotional Distress (Depression, Anxiety)
Physical Function
The PROMIS Metric
T Score
Mean = 50
SD = 10
Referenced to the US General
Population
PROMIS Fatigue Across Five Clinical Conditions
Cancer
w/ benefit
(2 mos)
N = 310
N = 229
Cancer
Chemo
(B)
Back PainBack Pain Back Pain
(3 mos) (1 mo)
(B)
Depression Depression Depression
(1 mo)
(3 mos)
(B)
N = 114
N = 64
HF Post-transplant
HF Pre-transplant
Exacerbation to Stable
N = 125
COPD Stable (B)
35
40
45
50
55
Average for General Population
COPD Exacerbation (B
60
65
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PROMIS® Profile Short Forms
(29-43-57 items)
8
6
4
Mental
Anxiety
29
Depression
28
Fatigue
95
Physical
Pain Interference
41
Sleep Disturbance
27
Physical Function
86
Social
Satisfaction with Roles
14
27
27
PROMIS® combines:
• Item Response Theory (IRT) and
Computer Adaptive Testing (CAT)
• Together, IRT and CAT provide precise
measurement
individual
symptoms
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Computerized Adaptive Testing (CAT)
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Integrates IRT with computers
to administer a PRO
instrument
• selects questions on the
basis of a patient’s
response to previously
administered questions
Master
title style is “adapted”
• measurement
to individual
• skips uninformative items
to minimize response
burden
• allows determination of
person’s standing on a
domain without a loss in
measurement precision.
Computerized Adaptive Tests
Question #1
3
low
physical
function
1
0
Question #3
2
2
1
-3
-2
-1
0
2
Question #2
1
high
physical
function
Questionnaire
with a high
precision AND a
wide range
Who uses CAT?
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CAT Starts with an Item
Bank
• Covers the whole range of the domain
• Items are “calibrated” (difficulty and
discrimination)
An item bank is a large
collection of items measuring a
single domain.
Any and all items can be used to
provide a score for that domain.
0
50
100
Physical Functioning Item Bank
Item
1
Item
2
Item
3
Item
4
Item
5
Item
6
Item
7
Item
8
Are you able to get in and out of bed?
Are you able to stand without losing your balance for 1 minute?
Are you able to walk from one room to another?
Are you able to walk a block on flat ground?
Are you able to run or jog for two miles?
Are you able to run five miles?
Item
9
Item
n
PROMIS® Adult Banks: v1.0
Domains
Emotional Distress – Anger
Emotional Distress – Anxiety
Emotional Distress – Depression
Fatigue
Pain – Behavior
Pain – interference
Physical Function
Satisfaction with Discretionary Social Activities
Satisfaction with Social Roles
Sleep Disturbance
Wake Disturbance (sleep related impairment)
Global Health
Items in
Bank
29
29
28
95
39
41
125
12
14
27
16
Items in
Short
Form
8
7
8
7
7
6
10
7
7
8
8
10
Child-Adult Linkage Studies
• Render child
and adult
editions
comparable
(i.e., same scale)
• Result: life
course outcome
assessment
PROMIS® Pediatric Banks: v1.0
Domains
Emotional Distress – Anger
Emotional Distress – Anxiety
Emotional Distress – Depression
Fatigue
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Pain – Interference
Physical Function-Mobility
Physical Function-Upper Extremity
Peer Relationships
Asthma
title
Items in
Bank
n/a
15
14
23
style
13
125
29
15
17
Items in
Short
Form
6
8
8
10
8
10
8
8
8
Assessment Center
www.nihpromis.org
- Download PROMIS
questionnaires
- Computerized Adaptive
Tests
-Study-specific URL
- Non-PROMIS items
- eConsent
- Data dumps
- NIH inclusion enrollment
report
AC supports different modes of
administration
Select CATs
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CAT demo results
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Contributions: Future Clinical Research
• Precision – improved measurement precision
across the full range of patient-reported
outcomes
• Efficiency – less respondent burden
• Standardization
– more
interpretable
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research with standard terminology and metrics
• International clinical trial applications
• Common language between research and
practice fosters CER
Rare Diseases: Opportunities
There are estimated to be 7000
rare diseases
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There are not 7000 PRO
instruments to measure them