Transcript From the Data to the Integrome. How fusing different data

Obtaining The Numbers Behind
the Translational Imperative
Harvard Medical School
Center for Biomedical Informatics
i2b2 National Center for Biomedical Computing
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Isaac S. Kohane, MD, PhD
John Glaser, PhD
Susanne Churchill, PhD
A National Center for Biomedical Computing
Example: PPARg Pro12Ala and
diabetes
Sample size
Oh et al.
Deeb et al.
Mancini et al.
Clement et al.
Hegele et al.
Hasstedt et al.
Lei et al.
Ringel et al.
Hara et al.
Meirhaeghe et al.
Douglas et al.
Altshuler et al.
Mori et al.
All studies
Estimated risk
(Ala allele)
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Overall P value = 2 x 10-7
Odds ratio = 0.79 (0.72-0.86)
0.2 0.4 0.6 0.8 1
1.2 1.4 1.6 1.8 2.0
0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9
Ala is protective
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Courtesy J. Hirschhorn
And here comes
commercialization (
MD’s not required
)
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QuickTime™and a
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Knome has launched the first
commercial whole-genome
sequencing and analysis service for
individuals for $350,000 per
genome. The sequence data will
undergo comprehensive analysis
from a team of….
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Common-Rare:Weak-Strong
Spectrum
Tay-Sachs
rare
CAD
common
ASD
106
patients
104
diseases
MODY
DM2
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102
diseases
Huntington’s
Deterministic
“highly penetrant”
108
patients
Weak effect, not predictive,
dominated by environment
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Dangers of Large N and small p(D)
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Q u ic k T im e ™ a n d a
T I F F ( Un c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
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Challenge: Efficiently Reach
Large N
• High throughput genotyping
• High throughput phenotyping
• High throughput sample acquisition
DHHS Secretary’s Advisory Committee on
Genetics, Health, and Society (SACGHS)
argues for the health value of a 500,000 to 1M
subject study. Estimated cost: $3,000,000,000
Cost of the pediatric 100,000 study recently
launched >> $1B + decades.
Infor matics for Integrating Biology & the Bedside
A National Center for Biomedical Computing
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Infor matics for Integrating Biology & the Bedside
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NLP (and comedy) is not pretty
SOCIAL HISTORY: The patient is married with four grown daughters,
Smoker
uses tobacco, has wine with
dinner.
SOCIAL HISTORY: The patient is a nonsmoker. No alcohol.
Non-Smoker
SOCIAL HISTORY: Negative for tobacco, alcohol, and IV drug abuse.
BRIEF RESUME OF HOSPITAL COURSE:
Past
Smoker
63 yo woman with COPD, 50 pack-yr tobacco (quit 3 wks ago), spinal
stenosis,
...
SOCIAL HISTORY: The patient lives in rehab, married. Unclear smoking history
from the admission note…
???
HOSPITAL COURSE: ... It was recommended that she receive …We also added Lactinax, oral
form of Lactobacillus acidophilus
to attempt
a repopulation of her gut.
Hard
to pick
SH: widow,lives alone,2 children,no tob/alcohol.
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Hard to pick
But it works
• 96,000 asthma patients identified out of
2.5M PHS patients
– Stratified by severity, pharmaco-responsiveness
and exposures
– Now with cases and controls (from extrema)
reconsented and biomaterials obtained for
genome-wide scans ++
– 3 methods of tissue acquisition
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Infor matics for Integrating Biology & the Bedside
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The three prongs of High
Throughput Instrumentation
• $250-$500 for 500,000 SNP’s
• $50-100K for good quality phenotyping of
100K++ individuals
• What about the samples (consented)
– $650/patient
• Dozens a week
– Wait in clinic: $450+/patient
• Crimson
– Lynn Bry, MD
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Crimson: Core Functions
Mined Phenotypes
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Matched
Anonymous
ID
Richly annotated biospecimens
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Clinical discard
Meeting Expectations
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Accrual Rates
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Costs
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Thank you
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