Directions in Collaborative Brain Injury Rehabilitation Research

1. Directions in Collaborative Brain Injury Rehabilitation Research John Whyte, MD, PhD Moss Rehabilitation Research Institute

2. Presentation Goals • Discuss the types of research that are relevant to brain injury rehabilitation • Examine what is required to successfully conduct those forms of research • Examine the types of research that can be conducted at a single institution, those that must be conducted collaboratively, and what is required for successful collaborations

3. Types of Research • Population-based epidemiology • Longitudinal natural history* • Prediction* • Descriptive clinical* • Development of measurement tools* • Treatment efficacy* • Enablement models • Health services • * = productivity for an individual clinical institution in at least some phases of the research

4. Population-based epidemiology • Aims to define the incidence or prevalence of a clinical problem in a representative population • Hospitals generally poorly suited to this kind of research because of referral/selection biases • Exceptions if there is a clear and operationalized referral policy (e.g., “all patients with X are referred to institution Y”) • Benefit: policy relevant information about the quantity and severity and regional variation of a problem • Role for an individual institution: limited because of “population based” issue

5. Longitudinal natural history • Aims to characterize the clinical course of a disease or problem as it currently exists; need not be population based if the starting cohort can be clearly defined • Example: pace and variation in recovery of consciousness among TBI patients with 30 days of coma or more • Benefit: what problems persist and what problems resolve over time? How variable is recovery? What factors contribute to that variability? Policy relevance and basis for planning treatment trials. • Role for an individual institution: exploratory research on a common problem

6. Prediction • Aims to identify early variables that predict later outcomes • Example: premorbid and injury variables that predict successful return to work after TBI • Benefit: • Practical prediction in a group for service utilization • Practical prediction in the individual for treatment decisions (uncommon) • Clues of mechanistically relevant variables (empirical prediction vs. causal attribution) • Role for an individual institution: exploratory prediction of a common outcome

7. Descriptive clinical • Aims to describe a particular clinical syndrome or problem in a defined population • Similar to longitudinal, but may be cross-sectional • Example: prevalence of “ICU neuropathy” among TBI patients with ICU stays > 2 weeks • Benefit: highlight the magnitude of a clinical problem, identify “risk factors” for that problem, basis for treatment studies • Role for an individual institution: exploratory assessment of a common problem

8. Development of measurement tools • Aims to design reliable, valid, and sensitive tools for measuring clinical phenomena of interest • Example: inter-rater reliability studies of the Moss Attention Rating Scale • Benefit: supports clinical descriptive, longitudinal, and treatment research by providing quantitative measures • Role for an individual institution: initial instrument development, exploratory psychometric research on measuring a common problem

9. Treatment efficacy • Aims to determine the clinical benefit of a particular treatment in a defined population • Example: a comparative study of a hand-held reminding computer vs. a “memory notebook” in supporting functional activities in TBI patients with memory deficits • Benefit: ultimate source of evidence to guide treatment selection • Role for an individual institution: proof of concept treatment development, initial feasibility and efficacy in a common problem

10. Enablement Models • Aims to quantitatively model the interrelationships among variables in the ICF • Example: What are the relevant contributions of lower extremity strength, balance, proprioception, and vision, in determining a patient’s ambulation ability? • Benefit: treatment efficacy research can identify tools to change specific clinical variables (e.g., strength), but cannot tell us in which patients improving strength will enhance ambulation. • Role for an individual institution: limited – generally requires a large sample with variation in the relevant impairments and functional activities of interest

11. Health services • Aims to understand how differences in healthcare delivery system organization, staffing, and financing are associated with differences in outcomes • Example: How are regional variations in rehabilitation length of stay and treatment intensity associated with functional outcomes? • Benefit: Addresses policy relevant issue in healthcare organization • Role for an individual institution: limited – it is the variation among providers that is useful; large samples required to control for “case mix”, etc.

12. Some Caveats • All research is developmental, meaning that a sequence of studies, rather than an individual study, ultimately answers the question(s) of interest. • A given institution may be very productive in participating in one developmental stage, and far less productive in another

13. Caveats (cont.) • “Studies that can be done at Hospital X” is not a domain of science! • Will hospital-trained researchers stay hospital-based? • Can a given hospital retain all the forms of expertise necessary to study all the topics of potential clinical interest? • Risks and benefits of un-linking the researcher from the research site • Benefit: allows a researhcer to “go where the science leads them” • Risk: it may lead them out of the institution

14. Two Examples

15. Assessment & treatment of TBI-related attention deficits • Review of existing research suggested the need for validated measures of the deficit • Development and testing of new measures (MRRI) • Computerized information processing tasks • Videotaped records of behavior in structured work settings • Determined that measures of processing speed, divided attention, and off-task behavior could be used • Pilot study of methyphenidate treatment, using those measures (MRRI)

16. Computer Testing Apparatus • Individualized durations • Pattern mask • Simple midline targets/foils • Most tasks similar with minor variations

17. Coding of Naturalistic Behavior • 3 independent visuo-motor tasks • Suitable for varied ability levels • Controlled distractions • Videotaping

18. Classroom Observation • Structured tasks • Group & individual work time • Free time • Time sampling w/ vibrating watches • Eye gaze, talking, location

19. Attention treatment (cont.) • Larger (34!!) methylphenidate crossover study (MRRI) • Next step: parallel group study – will require a multicenter system; that will require a new round of pilot work and problem solving • Problem: measures don’t address low level patients – develop a new observational measure

20. Attention treatment (cont.) • Develop observational rating scheme and items (MRRI) • Small inter-rater reliability study (MRRI) • Large inter-rater reliability study (multicenter) • Inter-rater reliability study on more disciplines (MRRI) • Validation against neuropsychological measures, etc. (MRRI) • Validation by treatment with methylphenidate (MRRI but should have been multicenter)

21. MARS

22. Treatment of disorders of consciousness • Preliminary feasibility exploration (MRRI assessing other sites) • All sites had low N, so strategy from the outset was multicenter • Longitudinal natural history and prediction study: what is the pattern of recovery and what factors account for variation? (multicenter) • RCT of amantadine vs. placebo: multicenter (N = 184)

23. Requirements for research productivity • Investigators with relevant expertise and a sustained interest • Adequate patient samples • Resources for data collection and, in particular, for follow up beyond clinical setting

24. Role of an individual institution • Provide patients: value is dependent on the size of the sample, and the “value” of the sample • Similar samples hard to find elsewhere • Samples elsewhere are not as well characterized • Value of a database or registry • A patient sample, alone, is rarely enough for a leadership role

25. Role (cont.) • Scientific leadership • What kind of scientific domain(s) are relevant? • Lead with “basic” science, or lead with “translational” science, e.g. – • The physiology and biological mechanisms of transcranial direct current brain stimulation on attention networks; vs. • The relationship between neglect and functional behavior

26. Questions to consider • What kinds of research (topic, phase) are feasible to conduct right now at this institution? • Patient sample • Scientific expertise & technical abilities • Clinical/translational knowledge • What kinds of research (topic, phase) would be feasible to conduct at this institution with “minor investments”?

27. Questions (cont.) • What kinds of research (topic, phase) that are being conducted by larger networks might have a role for this institution? • What kinds of research (topic, phase) could this institution lead by strategically developing collaborations with: • University scientists • Other clinical institutions • Government policy entities?

28. Summary • Almost all forms of rehabilitation research progress require a developmental sequence • Scientific needs vary over phases • Sample needs vary over phases • Difficult to identify a “scientific domain” that is well suited to a specific clinical institution across all developmental phases

29. Summary (cont.) • Take steps to enhance the “value” of the patient population(s) • Take steps to consolidate a team of internal investigators that are productive and valuable as collaborators • Enlarge the team with external investigators and collaborating clinical sites with similar interests • Accept that internal investigators will need to “go external” to follow scientific leads