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

Click to edit Master title style Goals of presentation General Overview The ‘science’ of PROMIS –Domain theory of disease –Item Response Theory (IRT) Application of Computerized Adaptive Testing (CAT) –Terminology Future in rare diseases

Click to edit Master title style Definitions-Terminology Items are questions that have: Context, stems, responses Parameters (Difficulty, Discrimination) –Important for analyses, calibration Banks (collection of items) “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

Click to edit Master title style 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 »Abilities »Attitudes Based on probability of endorsing a particular item category is function of latent trait or ability Ability to improve reliability of instrument

Low High Persons’ Levels of Physical Function Item Difficulty IRT models Latent Traits: People and Items are Represented on the Same Scale Are you able to run 5 miles Are you able to get out of bed. Low High 5

Click to edit Master title style DOMAINS A domain is the specific feeling, function, or perception you want to measure. Cuts across different diseases

Click to edit Master title style Evolving concept of health DOMAIN vs. DISEASE SPECIFIC

Click to edit Master title style Domains & Diseases: Hypotheses Rare diseases are combinations of different domains –fatigue, physical function, anxiety, pain… Capturing multiple domains may be optimal way to assess rare diseases Core-common PRO domains are universally applicable across diseases, ages and ethnicities Core PRO domains can link common and rare diseases

Click to edit Master title style Outcomes (FDA workshop & ICOAWG) Clinical Outcomes Assessments (COAs) PROs: Patient-reported outcomes ClinROs: Clinician-reported outcomes ObsROs: Observer-reported outcomes all influenced by human choices, judgment, cooperation or motivation Biomarkers not influenced by humans

Click to edit Master title style Patient-Reported Outcomes (PROs) FDA and NIH recognize PROs as important outcomes to answer clinical questions –translating the efficacy-effectiveness and safety of therapeutics 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)

Click to edit Master title style Advancing Patient-Centered Outcomes PROMIS: A Common Source of PROs Clinical Practice Clinical research Surveys (CDC) NIH FDA Clinic Hospital Industry

Click to edit Master title style NIH PROMIS

Click to edit Master title style PROMIS: Present

PROMIS Resources Advancing Knowledge >100 Peer-Reviewed Publications Informatics Assessment Center Supports >100 Studies Tools 40 Adult Measures 20 Pediatric Measures Translations All item banks  Spanish Cooperative Group 12 Research Sites 3 Centers 150+ Scientists

DOMAINS

Click to edit Master title style Common DOMAINS Fibromyalgia Pain, fatigue, depression SLE Fatigue, pain, social function RA Pain, physical function, fatigue

Anxiety Prostaglandins Interleukins Chemokines Sleep PROs Mechanisms Pain Phys Fn Social Fatigue

Fatigue Item Bank Lower Back Pain Same metric, same meaning Depression Heart Failure Cancer COPD

PROMIS Measures Tested in Six Conditions ConditionRelevant 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 Average for General Population COPD Stable (B) COPD Exacerbation (B) HF Pre-transplant HF Post-transplant Exacerbation to Stable Depression (B) Depression (1 mo) Depression (3 mos) Cancer Chemo (B) Cancer w/ benefit (2 mos) Back Pain (B) Back Pain (1 mo) Back Pain (3 mos) N = 64 N = 310 N = 114 N = 229 N = 125

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27 PROMIS ® Profile Short Forms ( items) 27 Anxiety 29 Anxiety 29 Depression 28 Depression 28 Fatigue 95 Fatigue 95 Pain Interference 41 Pain Interference 41 Sleep Disturbance 27 Sleep Disturbance 27 Physical Function 86 Physical Function 86 Satisfaction with Roles 14 Satisfaction with Roles Mental Physical Social

Click to edit Master title style PROMIS ® combines: Item Response Theory (IRT) and Computer Adaptive Testing (CAT) Together, IRT and CAT provide precise measurement of individual symptoms

Click to edit Master title style Computerized Adaptive Testing (CAT) Integrates IRT with computers to administer a PRO instrument selects questions on the basis of a patient’s response to previously administered questions measurement is “adapted” 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 high physical function Question #2 1 2 Question #3 Questionnaire with a high precision - AND a wide range low physical function Question #1

Who uses CAT?

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Covers the whole range of the domain Items are “calibrated” (difficulty and discrimination) CAT Starts with an Item Bank

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.

PROMIS ® Adult Banks: v1.0Domains Items in Bank ShortForm Emotional Distress – Anger 298 Emotional Distress – Anxiety 297 Emotional Distress – Depression 288 Fatigue957 Pain – Behavior 397 Pain – interference 416 Physical Function Satisfaction with Discretionary Social Activities 127 Satisfaction with Social Roles 147 Sleep Disturbance 278 Wake Disturbance (sleep related impairment) 168 Global Health 10

Child-Adult Linkage Studies Render child and adult editions comparable (i.e., same scale) Result: life course outcome assessment

Click to edit Master title styleDomains Items in Bank ShortForm Emotional Distress – Anger n/a6 Emotional Distress – Anxiety 158 Emotional Distress – Depression 148 Fatigue2310 Pain – Interference 138 Physical Function-Mobility Physical Function-Upper Extremity 298 Peer Relationships 158 Asthma178 PROMIS ® Pediatric Banks: v1.0

Assessment Center - 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

Click to edit Master title style Select CATs

Click to edit Master title style CAT demo results

Click to edit Master title style Contributions: Future Clinical Research Precision – improved measurement precision across the full range of patient-reported outcomes Efficiency – less respondent burden Standardization – more interpretable research with standard terminology and metrics International clinical trial applications Common language between research and practice fosters CER

Click to edit Master title style Rare Diseases: Opportunities There are estimated to be 7000 rare diseases There are not 7000 PRO instruments to measure them