Transcript Media:Gabriel072506

Candidate Gene Resource
Steering Committee Meeting
July 25, 2006
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
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
CARE : timeline
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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
Resources Provided by NHLBI
• $18.3M over 4 years to create a resource to
relate genotype-phenotype across cohorts:
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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
Areas for Discussion Today
• Data Release
NHLBI
• Study Design
Current state of
genotyping technology
• Phenotypes
Presentation of
informatics tools
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
Areas for Discussion Today
• Data Release
NHLBI
• Study Design
Current state of
genotyping technology
• Phenotypes
Presentation of
informatics tools
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
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
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
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
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
Coverage
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Do they work?
Affymetrix 500K
(Broad)
Illumina 317K
(CIDR*)
Samples
Average call
rate
1200
99.10%
1400
99.80%
* from http://www.cidr.jhmi.edu/human_gwa.html
Concordance with
Hap Map
48 CEU samples,
99.10%
8 CEU samples,
99.85%
Trio
concordance
60 trios, 99,9%
10 trios, 99.85%
Do They Work at High Scale?
Recent Call Rate Data
(at Broad)
In-Process QC test
HapMap sample vs Hap Map
CONCORDANCE (CNTRL VS HapMap, n=42)
Product
Chips
Call Rate
Affy 500K
ILMN 317K
12,000 98.7%
250 99.2%
100.00%
99.50%
99.00%
98.50%
98.00%
97.50%
0
5
10
15
20
25
30
Avg=99.62%
7,947,748 comparisons
35
40
45
QC statistics:
MS andT2D Scans
Samples attempted
Pass DM (0.26) >=85%
Pass BRLMM >=95%
MS Scan
Nsp
Sty
#
% of Total
#
% of Total
1530
100%
1558
100%
1474
96%
1476
97%
1438
94%
1428
93%
Avg call rate passing samples
99.10%
# Passing SNPs in passing samples
253,172
99.00%
97%
230,816
T2D Scan
Nsp
Sty
#
% of Total
#
% of Total
1117
100%
867
1%
1040
93%
817
94%
1008
90%
792
91%
99.00%
97%
251,248
98.70%
96%
228,972
96.10%
DM vs. BRLMM 2500 chips
<5% of chips fail
Genotyping Costs per Sample
$1,800
$1,600
Chip cost per sample
$1,400
$1,200
Affy 500K
ILMN 317K
ILMN 550K
ILMN 650Y
$1,000
$800
MIP (20K)
$600
$400
$200
$0
Jul-05
Oct-05
Jan-06
Apr-06
Aug-06 Nov-06
Feb-07
Jun-07
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
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
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
In Summary
SNPs
500,000
17,000
Samples
1,500
50,000
Cost
$2.4M
$8.5M
7/25/06
500,000
17,000
4,500
50,000
$2.4M
$8.5M
1/07
`
500,000
17,000
5,800
50,000
$2.4M
$8.5M
7/15/05
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
Areas for Discussion Today
• Data Release
NHLBI
• Study Design
Current state of
genotyping technology
• Phenotypes
Presentation of
informatics tools
High Level Workflow – for CaRE
Analysis: Gene Pattern +
Production:
CaRE analysis tools
BSP/GAP + CaRE enhancements
Create Experiments
(Samples x Features)
Project
DB
Feature
DB
Design and
Execute
Experiments
QC/Curate Results
Data Compile
BSP DB
Web Services
Upload Samples,
Peds, Individuals,
Phenotypes
LIMS DBs
Data Vault
Summarize/Filter
PLINK
Association &
Statistics Viewers
Cohort’s Custom
Algorithms, Viewers
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
CSSCD
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ARE
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Our shared aspiration: the
greatest genetic epidemiology
experiment to date
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Technological Advance
Current 500K assay
DNA
New 500K assay
DNA
How?
A/A
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A/B
B/B
Sequence Variability
Mismatch
probes
(DNA Analysis)
not needed
BRLMM
Single format
Smaller format
Fewer probes needed
No drop in Het Calls
Mendel Errors Per Plate
Accuracy 99.4%
Sty/Nsp : one family
25,000 errors
Coverage of Common Variants
by Whole-genome Products
Tag SNPs
Affymetrix Mapping 500K GeneChip
Illumina HumanHap300 BeadChip
Coverage Mostly Provided by
Pairwise Correlations
A
A
A
T
T
T
G
G
G
T
T
T
G
G
T
G
G
G
T
T
C
T
T
C
A
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C
A
A
C
T
T
G
T
T
G
G
G
C
C
C
C
G
G
C
C
C
C
G
G
T
T
G
G
G
G
C
C
C
C
G
G
T
T
G
G
A
A
A
A
T
T
C
C
C
C
T
T
G
G
T
T
G
G
C
C
C
C
G
G
A
A
A
A
C
C
Specified Multimarker Tests
Improve Effective Coverage
C
C
A
A
A
T
T
T
G
G
T
G
G
G
A
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C
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C
G
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C
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G
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T
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G
G
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T
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G
G
C
C
C
C
T
T
G
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T
T
G
G
Coverage of the genome
Fraction common SNPs
2
captured at r of 0.8
YRI Coverage
100%
80%
Single markers
2-marker predictors
60%
40%
20%
0%
Affy100k
Affy500k
Ilmn300k
Array
Ilmn550k
Fraction common SNPs
2
captured at r of 0.8
CEU Coverage
100%
80%
Single markers
2-marker predictors
60%
40%
20%
0%
Affy100k
Ilmn300k
Affy500k
Array
Ilmn550k
Other recent developments
• Whole genome scan planned in 9,000
FHS participants (SHARE)
• Other whole genome scans will be
funded (recent NHLBI RFA)