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Obtaining The Numbers Behind the Translational Imperative. Harvard Medical School Center for Biomedical Informatics i2b2 National Center for Biomedical Computing Isaac S. Kohane, MD, PhD John Glaser, PhD Susanne Churchill, PhD. Example: PPAR g Pro12Ala and diabetes. Oh et al. Deeb et al.

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obtaining the numbers behind the translational imperative

Obtaining The Numbers Behind the Translational Imperative

Harvard Medical School

Center for Biomedical Informatics

i2b2 National Center for Biomedical Computing

Isaac S. Kohane, MD, PhD

John Glaser, PhD

Susanne Churchill, PhD

example ppar g pro12ala and diabetes
Example: PPARg Pro12Ala and diabetes

Oh et al.

Deeb et al.

Mancini et al.

Clement et al.

Hegele et al.

Hasstedt et al.

Lei et al.

Ringel et al.

Sample size

Hara et al.

Overall P value = 2 x 10-7

Odds ratio = 0.79 (0.72-0.86)

Meirhaeghe et al.

Douglas et al.

Altshuler et al.

Mori et al.

All studies

Estimated risk

(Ala allele)

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

Courtesy J. Hirschhorn

and here comes commercialization md s not required
And here comes commercialization (MD’s not required)

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….

common rare weak strong spectrum

rare

Tay-Sachs

common

CAD

ASD

106

patients

108

patients

MODY

DM2

104

diseases

102

diseases

Huntington’s

Deterministic

“highly penetrant”

Weak effect, not predictive, dominated by environment

Common-Rare:Weak-Strong Spectrum
challenge efficiently reach large n
Challenge: Efficiently Reach LargeN
  • 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.

nlp and comedy is not pretty

SH: widow,lives alone,2 children,no tob/alcohol.

BRIEF RESUME OF HOSPITAL COURSE: 63 yo woman with COPD, 50 pack-yr tobacco (quit 3 wks ago), spinal stenosis, ...

SOCIAL HISTORY: Negative for tobacco, alcohol, and IV drug abuse.

HOSPITAL COURSE: ... It was recommended that she receive …We also added Lactinax, oral form of Lactobacillus acidophilus to attempt a repopulation of her gut.

SOCIAL HISTORY: The patient is a nonsmoker. No alcohol.

SOCIAL HISTORY: The patient is married with four grown daughters,uses tobacco, has wine with dinner.

SOCIAL HISTORY: The patient lives in rehab, married. Unclear smoking history

from the admission note…

Smoker

Non-Smoker

Past Smoker

???

Hard to pick

Hard to pick

NLP (and comedy) is not pretty
but it works
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
the three prongs of high throughput instrumentation
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
crimson core functions

Matched

Anonymous

ID

Richly annotated biospecimens

Mined Phenotypes

Clinical discard

Crimson: Core Functions