Obtaining The Numbers Behind the Translational Imperative

1. 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

2. 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

3. 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….

4. 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

5. Dangers of Large N and small p(D)

7. 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.

9. 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

10. 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

11. 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

12. Matched Anonymous ID Richly annotated biospecimens Mined Phenotypes Clinical discard Crimson: Core Functions

13. Meeting Expectations

14. Accrual Rates

15. Costs

16. Thank you