Cancer Genetic arkers of Susceptibility 遗传易感性标记.ppt

Initial Study for GWAS Cases and controls well matched with respect to ancestry to minimize population stratification (restriction to one self-identified group) Genomic control or other methods e.g. Eigenstrat (Price et al, 2006), may compensate for looser matching Control of population stratification e.g. hair colorin Nurses’ Health Study (European ancestry) Initial Study for GWAS: technical issues Standard advice – case and control samples handled exactly the same at every stage Source of DNA Blood/buffy coat mostly good results Buccal cell variable results (Feigelson et al. CEBP, 2007 - encouraging) Whole genome amplified DNA (Affy OK, Illumina in development) Replication studies For statistical replication, prefer: Similar phenotype Similar ancestry For generalizability, prefer Different populations Different ancestry backgrounds (may also help with fine mapping) Study design? Prospective Protect from survivor bias Protect from selection bias Interpretability of gene-environment analyses Possibility of interpretable biomarkers Study quality? Importance depends on strength of signal To date – little apparent relation between probability of replication and quality May matter more for weak signals Sample size may trump quality (within limits) NCI BPC3 Results: 7909 cases, 8683 controls Cancer Genetic Markers of Susceptibility (CGEMS): Committed Studies CGEMS CGEMS: caBIG Posting Pre-Computed Analysis Additional In silico replication possibilities dbGAP /dbgap Framingham /about/framingham WTCCC .uk DGI /diabetes CGEMS Acknowledgements NCI Stephen Chanock Gilles Thomas Robert Hoover Joseph Fraumeni Daniela Gerhard Kevin Jacobs Zhaoming Wang Meredith Yeager Robert Welch Richard Hayes Sholom Wacholder Nilanjan Chatterjee Kai Yu Margaret Tucker Marianne Rivera-Silva NCICB * Selecting Initial GWAS and replication studies David Hunter Harvard School of Public Health Brigham and Women’s Hospital Broad Institu