NIH Roadmap: Links from Basic to Services Research

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NIH Roadmap Links from Basic to Services
Research

• Robert M Bilder, PhD
• Semel Institute for Neuroscience Human
  Behavior Departments of Psychiatry
  Biobehavioral Sciences and Psychology, UCLA

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Molecular Libraries and Imaging
Re-engineering the Clinical Research Enterprise
Building Blocks, Biological Pathways and
Networks
Clinical Enterprise
New Pathways to Discovery
Structural Biology
Public-Private Partnerships
Implementation Groups
Bioinformatics and Computational Biology
High-risk Research
Interdisciplinary Research
Nanomedicine
Research Teams of the Future
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Why Interdisciplinary Research?

• The scale and complexity of today's biomedical
  research problems demand that scientists move
  beyond the confines of their individual
  disciplines and explore new organizational
  models of team science.

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Exploratory Centers P20 21 awards 12.3M
Meetings and Networks for Methodological
Development in Interdisciplinary Research R13
and R21 9 awards 950K
Interdisciplinary Health Research Training
Behavioral, Environment, and Biology T32 3
awards 600K
Training a New Interdisciplinary
Research Workforce T90 17 awards 5.2M
Interdisciplinary Research FY2004 23M
Short Programs for Interdisciplinary
Research Training R13 6 awards 1.2M
Supplements for Methodological Innovations in the
Behavioral and Social Sciences 15 awards 1.6M
Curriculum Development Awards K07 9 awards 1.0M
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EXPLORATORY CENTERS (P20) FOR INTERDISCIPLINARY
RESEARCH
Integrate different disciplines to open currently
unimagined scientific avenues of inquiry, and in
the process, form new disciplines Research
Teams of the Future
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P20 Program Interdisciplinary Centers

• More than 150 applications
• 21 exploratory centers established
• Broad geographic distribution
• Topics range from entomology, through obesity, to
  health services disparities
• UCLA Center for Cognitive Phenomics (CCP)

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The Human Phenome Project

• Human Genome Project is now complete
• New databases are rapidly being developed to
  represent gene expression, proteomic knowledge
  (bottom-up approach)
• The main hurdle for biomedical science for the
  next century is the Human Phenome Project1
  characterizing the manifold human phenotypes from
  molecule to mind

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1Freimer Sabattini, Nat Genet 2003
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Cognitive Phenotyping for Neuropsychiatric
TherapeuticsP20 RR020750
http//www.phenomics.ucla.edu
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What is (are) Cognitive Phenomics?

• Phenomics discipline dedicated to the study of
  phenotypes (integrating measurement theory,
  bioinformatics, and biology)
• Cognitive phenomics (broad) study of
  brain-related phenotypes (in CCP, relevant to
  neuropsychiatric therapeutics)
• Requires
• Bioinformatics architecture capable of supporting
  traversals across diverse data types (brain
  images, cognitive experiments, symptoms and
  syndromes)
• Experimental approaches using multiple methods in
  multiple species

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What are the goals of the Center for Cognitive
Phenomics?

• Multi-level modeling of latent constructs
  (endophenotypes) and relationships among
  constructs
• Literature mining (publication-based data)
• Data mining (case-based data)
• Hypothesis and model testing
• Provide infrastructure for translational
  validation of putative endophenotypes across
  disorders and species

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CCP Investigative Team

• 28 Investigators at UCLA
• UCLA NPI (Psychiatry, Neurology), Psychology,
  Human Genetics, Engineering/Computer Science
  (Bioinformatics), Public Health
• 70 NIH grants across 13 institutes and centers
  NIMH, NIDA, NIA, NINDS, NCRR, HGRI, NIDDK, NIBIB,
  NEI, NIGMS, NICHHD, NHLBI, AHRQ

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Consortium Schematic Themes
H.T. PHENO- TYPING
FUNCTIONAL MOLECULAR IMAGING
NEURO- PSYCHO- PHARM
BIO- INFORMATICS MODELING
IMPULSIVITY-RESPONSE INHIBITION
MEMORY
Long-Term/Declarative Memory
Short-Term/Working Memory
Procedural Learning/Habit Memory
CEREBRAL ASYMMETRY/COMMUNICATION
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AHSR Conference Goals to address social,
political, fiscal, regulatory, environmental, and
other factors affecting the processes and
outcomes of drug/alcohol abuse prevention,
treatment, and related health services"
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Factors limiting impact of basic science on
services

• Social
• Barriers preventing consumers from accessing
  science knowledge
• Barriers preventing basic scientists from
  contributing to services research
• Regulatory
• Logjam among FDA, industry, and academia

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Obstacle Inertia of Neuropsychiatric Diagnosis
in Drug ( Gene) Discovery
Academia Uses DSM to increase reliability
assure relevance to clinical practice
Industry Conforms to FDA regulatory guidance and
precedents
Clinics
Insurers
FDA Relies on clinically accepted and
academic definitions of syndromes
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Solution Provide New Focus on Biologically
Plausible Targets for Drug ( Gene) Discovery
Academia Revise DSM make links to alternate
phenotypes provide new evidence appropriate to
FDA focus industry on novel biomarker validation
Industry Can support development of new
biomarkers validate new approaches in POC studies
FDA Can assess new evidence particularly if
supported by mechanistic hypotheses
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How can phenomics impact services research?

• Reconceptualization of target phenotypes and
  treatment targets
• Refine measurement methods for application in
  clinical trials and community settings
• Develop informatics architecture that connects
  biological knowledge discovery with medical
  informatics

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What do we service?
Syndrome
Services
Symptoms
Cognitive Phenotype
If we can validate links from syndrome through
genome, then service delivery can be rationally
targeted to maximize patient and societal benefits
Neural System
Cell System
Protein
Gene
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Reconceptualization of target phenotypes and
treatment targets

• Existing diagnostic taxonomy is a barrier to
  scientific discovery so treatable phenotypes are
  not investigated
• Biologically invalid disorders pose artificial
  distinctions for service delivery systems
• Example amphetamine dependence vs.
  impulsivity/response inhibition deficit

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Refine measurement methods for application in
clinical trials and community settings

• High-throughput phenotyping optimize
  measurement methods to enable valid construct
  assessment with minimum time
• Identify constructs that link ecological targets
  to basic science mechanisms
• Develop innovative approaches (e.g., web-based
  assessment, clinic service centers) to collect
  larger service-relevant samples

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Develop informatics architecture that connects
biological knowledge discovery with medical
informatics

• Medical Informatics and Health Services Research
  Bridging the GapJanuary 6-7, 2000
• National Library of Medicine (NLM)
• Agency for Healthcare Research and Quality (AHRQ)
  
• Primary gap between (bioinformatics and imaging
  informatics) and (medical informatics)

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Conclusions

• Chasm from basic to services is wide, deep
• NIH Roadmap offers ramps, not bridges
• Links among Research Teams of the Future,
  Clinical Enterprise, and New Pathways to
  Discovery can be developed
• Phenomics (informatics, new phenotype definition)
  may help forge links

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