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Data Driven Neuropsychiatric Profiling
Qualifying Exam PresentationVanessa SochatAugust 19, 2013
Why do we need a model of disorder?Treatment hinges on diagnostic subtypes
patient assessment
autismADHDbipolar
schizophrenia
diagnosis of
bipolar
treatment
education
finances
research
?diagnosi
s of bipolar
treatment
education
finances
research
The Diagnostic and Statistical Manual of Mental Disorder (DSM)
“loss of interest”“depressed mood”“insomnia”“excessive sleeping”
depression
anxiety
PTSDdepressio
n
autismADHD
bipolar
Autism Spectrum Disorder (ASD):A childhood development disorder
• Afflicts 1 in 100 children • Economic burden of $126 billion annually• Social, communication, and cognitive deficits,
repetitive behaviors and interests
data-driven subtyping of autism spectrum disorders for early diagnosis and tailored, effective treatmentAutism
Asperger’s
PDD-NOS
DSM IV
Autism
DSM V
Unsolved Problem:
data-driven subtyping of neuropsychiatric disorder for early diagnosis and tailored, effective treatment
How might we model disorder?
Genetics
Behavior
Neuroimaging
combinations of genes small effects high heritability a marker of risk, not certainty
biased and unreliable
brain phenotype to define disorder?
Goal
A new model of neuropsychiatric disorder based on patterns of local brain structure
neuropsychiatric profile
brain phenotyp
e
cognitive phenotyp
e
Hypothesis
Mining imaging data will define clinically-useful disease subtypes better than currently possible
using DSM alone.
Aim1: to develop a computational representation of brain phenotype, and use it to define subtypes of neurological disorder
Aim 2: to create a structured normalized representation of cognitive phenotype as a new standard for evaluationAim 3: to evaluate by reproducing known brain-behavioral relationships, and finding subtypes of autism
Specific Aims
Aim1: to develop a computational representation of brain phenotype, and use it to define subtypes of neurological disorder
brain phenotyp
e
cognitive phenotyp
e
DISORDER HEALTHYCONTROL
Start with groupsCollect dataFind differencesInconsistent results
How do we find brain-based differences?
1234
Assumptions about the brain
Assumptions about the groups
How do we find brain-based differences?
make assumptions about spatial meaningfulness voxel-wise features prime to overfitting
diagnostic categories represent homogenous syndromes what about heterogeneity of the healthy controls?
learn groups from the data
make no assumptions about spatial location strive for an abstraction of structure
Collect dataLocal brain phenotypeDefine groupsFind Differences
MRI
How should we find these differences?
1234
1
GROUP A GROUP B4
2
3
groups == proposed subtypes
Aim 2: to create a structured normalized representation of cognitive phenotype as a new standard for evaluation
brain phenotyp
e
cognitive phenotyp
e
BEHAVIORAL & COGNITIVE METRICS
Structure and normalize dataLink to specific traitsCreate cognitive phenotypes
Assessment metrics reflect human traits
123
Assessment 1
Q1…Q10 “Anxiety”
Assessment 2
Q30…Q40 “Anxiety”
2
IQ
anxiety, attention …
T1 T2 T3 …. TN
1
3cognitive phenotyp
e
Aim 3: to define and evaluate subtypes of autism spectrum disorderAim 3: to evaluate by reproducing known brain-behavioral relationships, and finding subtypes of autism
brain phenotyp
e
cognitive phenotyp
e
C1 C2 C3 …. CN
Evaluation of Brain Phenotype:Reproduce known Brain-Behavior Relationships
C1 C2 C3 …. CNT1 T2 T3 …. TN
0.20.50.7
2.9 0.20.1 1.97.2 2.1
Person APerson BPerson C
X1 X2 Y
ClusteringASD
CONTROL
Evaluation of Method:Show that we capture current gold standard
my groupsDSM
Evaluation of Method:Show greater homogeneity in our groups
different
similar
ASD CONTROL
GROUP A GROUP B
my groups
DSM
Evaluation of Method:Show more robust group differences
significant differences?
vs
vs
Summary:Data-driven neuropsychiatric profiling
patient
brain phenotype
MRI diagnosis
treatment
education
finances
research
Future Vision:Extension to other disorders and data types
brain phenotyp
e
AutismWhite MatterADHDBipolar
Gray MatterGene Expression
EHRdoctor visitsi-phone app
geneticmolecularclinical
cognitive phenotyp
e
Informatics Contribution
• Tools to extend Big Data paradigms to neuroscience
• Data-driven model of neuropsychatric profile• Brain phenotype• Cognitive phenotype
• Methods to define subtypes of disorder
Biological Contributions
• Discovery of biomarkers of disorder• Definition of disorder subtypes• Enabling personalized treatment
Acknowledgements
Advisors and PanelDaniel RubinRuss AltmanMark MusenAntonio Hardan
ColleaguesKaustubh SupekarFeature GroupThe MIND Institute
Support StaffJohn DiMarioMary Jeanne & Nancy
FundingMicrosoft ResearchSGF and NSF
Friends and Fellow BMIFrancisco GimenezRebecca SawyerLuke Yancy Jr.Beth PerchaKatie PlaneyTiffany Ting LuLinda SzaboDiego MunozJonathan MortensenThe M&Ms previously known as first years
Thank you!
2
anxiety, attention …
C1 C2 C3 …. CNAssessment X
Subscale Y “Anxiety”
Assessment A
Subscale B “Anxiety”
Cognitive Phenotypes for N = 26
…are meaningful about groups
(OBSERVED DATA)
(MIXING MATRIX) (ORIGINAL DATA)
X = A SX
n x m n x n n x m
fMRI data
time
time
space spacecomponents
components
spatial maps
How do we discover local brain structure?Matrix Decomposition
n x m n x n n x m
How do we discover local brain structure?Matrix Decomposition
sMRI data
brains
brains
components
components
space space
spatial maps
2.9 0.2 1.9brain
phenotype
Clustering GROUP 1
GROUP 2
How do we define subtypes?
GROUP 3GROUP 4
BEHAVIORAL & COGNITIVE METRICS
1. Collect data2. Covariate or control3. Data not used
How do we use assessment metrics?
123
A Mapping from Assessments to TraitsMapping Assessments to TraitsThe Cognitive Atlas
Mapping Assessments to TraitsThe Cognitive Atlas
Mapping Assessments to TraitsThe Cognitive Atlas
Representation Based on TraitsThe Cognitive Phenotype
1 32
Assessment X Subscale X “Anxiety” .04 Subscale Y “Attention” .90
Normalized Score =Total - Raw
Total
3
Representation Based on TraitsThe Cognitive Phenotype
C1 C2 C3 …. CN
Find all assessments for person LOUIE…
4
Find me a cohort defined by anxiety > .5
Are anxious people also impulsive?
brain phenotyp
e