Candidate Gene Resource Steering Committee Meeting July 25, 2006

1. Candidate Gene Resource Steering Committee Meeting July 25, 2006

2. Goals for Today • Strengthen relationships among CARE investigators • Define pilot project (phenotypes & SNPs) • Establish principles of data release • Discuss genotyping study design • Select phenotypes to be analyzed

3. CARE Governance • Steering committee • Representative of each CARE organization • Subcommittees : Data Release, Phenotypes, Study Design, Informatics, SNP Selection, DNA/Genotyping • NHLBI staff • NHLBI appointed oversight committee

4. CARE : timeline • RFP released March 2005 • Response submitted July 15, 2005 • Awarded April 1, 2006 • Four year award • Y1: Create DNA and phenotype database • Y2: Genotyping • Y3 / 4: Joint analysis and data distribution

5. Resources Provided by NHLBI • $18.3M over 4 years to create a resource to relate genotype-phenotype across cohorts: • Create a consortium among CARE cohorts • Database DNA and phenotypes • Genotype a common set of SNPs across cohorts • Create software tools to enable joint analysis • Data distribution as per CARE data release policy • Project management and coordination -PM hired : Deb Farlow

6. Areas for Discussion Today • Data Release • Study Design • Phenotypes NHLBI Current state of genotyping technology Presentation of informatics tools

7. Data release • Data release policy to be established by CARE steering committee with NHLBI and local IRB’s • Broad proposed secure, HIPAA compliant web architecture to implement this policy and to enable access-controlled environment for data sharing and analysis

8. Current state of genotyping technology Areas for Discussion Today • Data Release • Study Design • Phenotypes NHLBI Presentation of informatics tools

9. Original CARE Study Design • Candidate Gene Study • 50,000 samples • average 10 SNPs/gene x 1700 genes = 17,000 SNPs • Requirement: $0.01 /genotype (fully loaded) • Whole Genome Association Study • 500 cases / 1,000 controls • At least 300,000 SNPs genome wide

10. Candidate gene study • Targeted genotyping technology has remained stable : same price and throughput as in approved proposal • Key issue: criteria for selecting 17,000 candidate gene-based SNPs • biological hypotheses

11. Developments since RFP • Whole genome scans promise new hypotheses for candidate genes • Evaluation of coverage / performance of whole genome arrays • Price for whole genome genotyping technology has improved

12. Whole genome scanning • SHARE will genotype 15,000 people from NHLBI cohorts (FHS and TBA) • RFA for 4-5 whole genome scans • GAIN, WTCCC, etc, etc • Implication: hypotheses that could be confirmed and extended by CARE • Challenge: timing doesn’t synch up well with original CARE timeline

13. Developments since RFP • Whole genome scans promise new hypotheses for candidate genes • Evaluation of coverage / performance of whole genome arrays • Price for whole genome genotyping technology has improved

14. Coverage

15. Do they work? * from http://www.cidr.jhmi.edu/human_gwa.html

16. Product Chips Call Rate Affy 500K 12,000 98.7% ILMN 317K 250 99.2% Do They Work at High Scale? Recent Call Rate Data (at Broad) In-Process QC test HapMap sample vs Hap Map Avg=99.62% 7,947,748 comparisons

17. QC statistics: MS andT2D Scans

18. DM vs. BRLMM 2500 chips <5% of chips fail

19. MIP (20K)

20. WGAS: Then and Now Original Plan Product: Affymetrix 500K Total cost per sample: $1600 (chip+reagents+equipment+labor+IDC) Study Design: 500 cases / 1,000 controls Budget=$2,400,000

21. WGAS: Then and Now Now possible Product: Affymetrix 500K Total cost per sample: $530(chip+reagents+equipment+labor+IDC) Study Design: 4,500 samples Budget=$2,400,000

22. WGAS: Then and Now January 2007 Product: Affymetrix 500K Total cost per sample: $410(chip+reagents+equipment+labor+IDC) Study Design: 5,800 samples Budget=$2,400,000

23. In Summary SNPs Samples Cost 7/15/05 500,000 1,500 $2.4M 17,000 50,000 $8.5M 7/25/06 500,000 4,500 $2.4M 17,000 50,000 $8.5M 1/07 500,000 5,800 $2.4M ` 17,000 50,000 $8.5M

24. Conclusions: genotyping • Targeted genotyping (custom set of candidate genes) stable @ $0.01 / gt • Timing of candidate gene selection • Improved cost and performance of whole genome arrays @ $0.001 / gt

25. NHLBI Current state of genotyping technology Areas for Discussion Today • Data Release • Study Design • Phenotypes Presentation of informatics tools

26. High Level Workflow – for CaRE Analysis:Gene Pattern + CaRE analysis tools Production: BSP/GAP + CaRE enhancements Upload Samples, Peds, Individuals, Phenotypes BSP DB Data Compile Summarize/Filter PLINK Project DB Create Experiments (Samples x Features) Web Services Association & Statistics Viewers Feature DB Design and Execute Experiments LIMS DBs Cohort’s Custom Algorithms, Viewers Data Vault QC/Curate Results

27. Designing a Pilot • A trial run for DNA quality, genotyping, phenotype and joint analysis, and publication • Scale and content of pilot to be refined, topic for today’s discussion sessions

28. CSSCD C A R E Our shared aspiration: the greatest genetic epidemiology experiment to date

30. Technological Advance Current 500K assay New 500K assay DNA DNA

31. A/A A/B B/B Sequence Variability (DNA Analysis) How? Mismatch probes not needed BRLMM Single format Smaller format Fewer probes needed

32. No drop in Het Calls

33. Mendel Errors Per Plate Accuracy 99.4% Sty/Nsp : one family 25,000 errors

34. Coverage of Common Variants by Whole-genome Products Tag SNPs Affymetrix Mapping 500K GeneChip Illumina HumanHap300 BeadChip

35. Coverage Mostly Provided by Pairwise Correlations A G G T A T G G G G G A C G C A A G G T A T G G G G G A C G C A A G T C C G C C T C T A C T C A T T G T A T C C T C T A C T C A T T G T A T C C G C G T T G G C T T G C C G C C G C G T T G G C

36. Specified Multimarker Tests Improve Effective Coverage C C A G A G G G C G A G A G G G C G A T C C T T C T T G A C T T C T T G A C G G T G T G C C G G T G

37. Coverage of the genome

39. Other recent developments • Whole genome scan planned in 9,000 FHS participants (SHARE) • Other whole genome scans will be funded (recent NHLBI RFA)