# Presentation: 472314

## Promoting Collaborations Across Studiesfor Replication and Follow-up Studies

**Robert N. Hoover, M.D., Sc.D**
**Director**
**Epidemiology and Biostatistics Program**
**June 22, 2007**

## Outline

**MEETING THE REQUIREMENTS FOR GOOD SCIENCE**
**Extent of Collaboration**
**Leadership Roles**
**Resource Enhancement**
**Training**
**Institutional Incentives**

## GWAS:  WHAT WORKS

******	****Replication, replication, replication (planned and coordinated)**
******	****Rigorous, high-quality design, conduct, analysis  **
**Genomics**
**Epidemiology**
**Statistics**
**Informatics**
**Data sharing**
**Accomplished Through Consortia**

**GWAS:  WHAT WORKS**

## Review of Genetic Association Studies

- 603 associations of polymorphisms and disease
- 166 studied in at least three populations
- Only six seen reproducibly (>75% of studies)

- Hirschhorn et al., Genetics in Medicine, 2002

**Notes:**
This can be seen again in the review by Hirschorn, which found that of 603 associations of polymorphisms and disease, only 166 were studied in at least three populations, and only six were seen reproducibly.

## Interaction of NAT2 and Active Cigarette Smoking in Breast Cancer Risk

| Study Year | # of Cases | Smoking Group | Subgroup | NAT2 ↑ risk group |
| --- | --- | --- | --- | --- |
| 1996 | 304 | All | Postmenop | Slow |
| 1997 | 466 | Former | All | Rapid |
| 1998 | 498 | Recent | Postmenop | Rapid |
| 2000 | 113 | --- | --- | None |
| 2000 | 177 | All | Postmenop | Rapid |
| 2001 | 149 | All | All | Rapid |
| 2002 | 442 | Recent | ≤50 yrs. | Slow |

-             # of cases         		# of SNPs
-             Tier 1    443                   198,000
-             Tier 2    332                   1800
- “We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect.” (Maraganore et al)

- “In this issue, four investigative teams ...have sought to replicate the findings from a GWA study of PD by Maraganore et al.  Taken together these four studies appear to provide substantial evidence that none of the SNPs originally featured as potential PD loci are convincingly replicated and that all may be false positives.”

## Study Size to Detect a Two-Fold Interaction

**Study Size to Detect a Two-Fold Interaction**

**True prevalence of exposure **

**No. of cases (=No. of controls) **

**Prevalence of genotype=10%**
**Exposure specificity=100%**

**Exposure sensitivity = 100%**

**Exposure sensitivity = 80%**

**Exposure sensitivity = 60%**

## Power of genome wide screen as a function of the number of retained false positive

**Power of genome wide screen as a function of the number of retained false positive**

- Model :
- One susceptibility allele : MAF = 0.1 , Odds Ratio = 1.4
- LD of typed marker with susceptibility marker : r2 = 0.8
- Number of cases/control pairs : 1,200
- Number of markers types : 500,000

- Number of false positives

- Power

## Lung Cancer Risk and CYP2D6*

|  | Study 1 | Study 2 | Study 3 |
| --- | --- | --- | --- |
| Relative Risk | 15. 6 (4.8 – 55.9) | 6.1 (2.2 – 17.1) | 0.6 (0.3 – 1.2) |
| Epidemiologic Quality | Low | Intermediate | High |
| (% participation) | (?) | (26%) | (80%) |

*** Risk of homozygous extensive metabolizers compared to homozygous poor metabolizers.**

**STUDY QUALITY**

## GWAS:  WHAT WORKS

******	****Replication, replication, replication (planned and coordinated)**
******	****Rigorous, high-quality design, conduct, analysis  **
**Genomics**
**Epidemiology**
**Statistics**
**Informatics**
**Data sharing**
**Accomplished Through Consortia**

**GWAS:  WHAT WORKS**

**MEETING THE REQUIREMENTS FOR GOOD SCIENCE**
**Extent of Collaboration**
**Leadership Roles**
**Resource Enhancement**
**Training**
**Institutional Incentives**

## Breast Cancer Association Consortium

**Breast Cancer Association Consortium**

**Cases**

**20 studies:**
**28,000 cases 30,000 controls**

## Breast Cancer Association Consortium: Findings to Date

**Breast Cancer Association Consortium: ****Findings to Date**

**20 candidate SNPs**
**(published + unpublished)**

**Some evidence**

**No association**
***ADH1C***** I350V**
***AURKA***** F31I**
***XRCC1***** R399Q**
***LIG4***** D501D**
***BRCA2***** N372H**
***XRCC3***** T241M**
***XRCC3***** 5’UTR**
***XRCC3***** IVS5**
***XRCC2***** R188H**
***ERCC2***** D312N**
***TP53***** R72P**
**BCAC, JNCI (2006)**

**9 SNPs**

**11**** ****SNPs**

**Strong**
***CASP8***** D320H**
**(P=1x10****-7****)**

**No association**
***SOD2 *****V16A**
***ADH1B *****3’UTR**
***CDK1A *****S31R**
***ICAM5 *****V301I**
***NUMA1 *****A794G**

**Reasonable **
***TGFB1 *****L10P**
**(P=0.0001)**
**(ER-, PR- tumors)**

**Moderate **
***IGFBP3 -202***
**(p=0.05)**
***ATM *****S49C**
**(p=0.09)**

**9-15 studies: 10,783 cases, 18,312 controls**

**Cox A/Dunning AM/Garcia-Closas M for the BCAC **
**Nat Genet 2007;39:688**

**Follow-up**

## 25+ cohorts, over 2.6 million individuals (1.2 million with DNA collected at baseline)

- CGEMS

- PanScan

- BPC3

- _Cohorts_: ATBC, CPS II, EPIC, HPFS, MEC, NHS, PHS, PLCO, WHS
- _Risk Factors_: Hormone risk factors and hormones
- _Genes_: 53 in steroid hormone and growth factor pathways
- _Cancer Sites_: Breast & Prostate cancer
- _Cases with DNA_:
- _Website_:
- _[http://epi.grants.cancer.gov/BPC3](http://epi.grants.cancer.gov/BPC3)_

- _Scan_: PLCO, NHS
- _Replication_: ATBC, CPS II, EPIC, HPFS, MEC, PHS, WHS, WHI
- _Risk factors_: Same as BPC3 plus family history
- _Genes_: Genome-wide Association Study (GWAS)
- _Cancer Sites_: Breast & Prostate cancer
- _Cases with DNA_: 8,850 breast cases, 6,160 prostate cases
- _Data Portal_:
- _[https://](https://caintegrator.nci.nih.gov/cgems/)__[caintegrator.nci.nih.gov/cgems](https://caintegrator.nci.nih.gov/cgems/)__[/](https://caintegrator.nci.nih.gov/cgems/)_

- _Scan_: ATBC, CLUE II, CPS II, EPIC, HPFS, NHS, NYUWHS, PHS, PLCO, SMWHS, WHI, WHS
- _Replication_: Pancreatic Cancer Case-Control Consortium (PANC4)
- _Risk Factors_: Tobacco, obesity, family history and diabetes
- _Genes_: Genome-wide Association Study (GWAS)
- _Cancer Sites_: Pancreatic cancer
- _Cases with DNA_: ~1,900 pancreatic cases
- _Website_:
- _[http://epi.grants.cancer.gov/PanScan/](http://epi.grants.cancer.gov/PanScan/)__ _

## Results: Overall in BPC3

***rs#1447295***

## Extent of Collaboration

**Limited Replication or More**
**Main Effects**
**Fine Mapping**
**Gene X Gene **
**Gene X Environment**
**Candidate Pathways**
**Other Phenotypes and Outcomes**

## Flow of Investigation: From Genome-Wide Association to Clinical Translation

**Sequencing/Genotyping**

**Functional Studies**

**Translational Studies**

_**   **_

** **

** **

** **

** **

** **

**Initial Genome-Wide**
**Association (GWA) Studies**

** **

** **

**Replication/Fine Mapping**

** **

** **

** **

** **

** **

** **

## 8q24 Region

**rs979200**

**rs1456310**

**rs1016343**

**rs6470494**

**rs13281615**

**rs16902124**

**rs10808555**

**rs6983267**

**rs7837328**

**rs1447295**

**rs7837688**

**129.0 M**

**127.6 M**

**MYC**

**rs10505476**

- CGEMS region 1

- CGEMS region 2

- CGEMS region 3

- CGEMS region 4

- CGEMS region 5

- CGEMS region 6

- CGEMS region 7

- CGEMS region 8

**rs132544738**

**rs6983561**

**rs7824074**

- Cancer Susceptibility

## Alcohol Consumption and NHL a Pooled InterLymph Analysis

| Risk of NHL subtypes associated with alcohol consumption |  |  |  |
| --- | --- | --- | --- |
|  | CLL/SLL
(N=814) | Diffuse
(N=1972) | Follicular
(N=1194) |
| Alcohol exposure | OR (95% CI) | OR (95% CI) | OR (95% CI) |
| Nondrinker | 1.00 | 1.00 | 1.00 |
| Ever drinker | 0.90 (0.75, 1.09) | 0.74 (0.66, 0.84) | 0.83 (0.71, 0.95) |
|     Current | 0.81 (0.59, 1.10) | 0.63 (0.52, 0.76) | 0.80 (0.64, 1.00) |
|     Former | 1.05 (0.69, 1.60) | 0.92 (0.72, 1.18) | 0.94 (0.69, 1.27) |

- Morton LM et al. – 2005 Lancet Oncology

## Leadership Roles

_**Leadership**_
**Shared**
**Complementary****	****	****	****Study Conduct**
**Apportioned****	****	****	****	****Analysis and Publication**

## InterLymph Organization

**Behavior and Environment****	****Host and Genetics**
**Executive Committee**
**Immunity and Infection**		**Pathology and ****	****	****	****	****	****	****Survival**

## BPC3 Organization

**	****Data Pooling****	****	****Publications**
**Steering Committee**
**Population****	****	****Genotyping****	****	****Statistics**
**Genetics****	****	**

## Publication Leadership

**Interlymph Consortium Publications**
**2005-2007**
**Number:****	****	****	****	****	****	****17**
**Number of different 1****st**** authors:****	****13**
**Number of different last authors:****	****14**

## Resource Enhancement

**Infrastructure – extraction, additional specimens or data, biomarkers**
**Additional Genotyping**

## Institutional Incentives

_**Investigator’s Institution**_
**	****- Promotion/Tenure**
**	****- Infrastructure**
_**Funding Institutions**_
**	****- Support for Consortia**
**	****- Targeted funding opportunities**
**	****- Base support for contributing studies**