PHARMACOGENOMICS ANALYSIS LABORATORY

1. PHARMACOGENOMICS ANALYSIS LABORATORY Cooperative Studies Program (CSP) Office of Research & Development, Department of Veterans Affairs Central Arkansas Veterans Healthcare System (CAVHS) Little Rock, AR

2. CSP ORGANIZATION VETERANS HEALTH ADMIN Office of Research & Development Biomedical Laboratory R&D Clinical Science R&D Health Services R&D Rehabilitation R&D Cooperative Studies Program Pharmacogenomics Analysis Laboratory (PAL)

3. CSP MISSION To advance the health and care of Veterans through collaborative research studies that produce innovative and effective solutions to national healthcare problems.

4. CSP OVERVIEW • CSP is a national infrastructure for sponsoring, developing & executing: • Multi-site clinical trials • Epidemiological & population research • Genomics research • First Cooperative Study conducted in 1940s on streptomycin for treating tuberculosis in WWII veterans • Program formally established in 1972 • Over 175 clinical trials and observational studies completed including landmark studies in cardiovascular disease / cardiovascular surgery, infectious diseases, surgery, gastroenterology, mental health, oncology, and endocrinology.

6. CSP CENTER LOCATIONS Seattle, WA Boston, MA West Haven, CT Perry Point, MD Hines, IL Washington, DC Palo Alto, CA Durham, NC Little Rock, AR Albuquerque, NM

7. VA Genomic Medicine Program • In 2006, the Department of Veterans Affairs launched the Genomic Medicine Program: • to examine the potential of emerging genomic technologies • to optimize medical care for veterans • to enhance the development of tests and treatments for relevant diseases

8. Genomic Medicine Program Con’t • Genomic Medicine Program Advisory Committee • Veterans’ Consultation Project • 83% supported; 71% willing to participate • Scientific Projects • Investigator-initiated • Large scale cohorts (SMI, PTSD, ALS) • Million Veteran Program (non-disease based)

9. Infrastructure Development • Expansion of Biorepository • CSP DNA Bank (~30,000 samples) • Expansion to ~4M; robotic store; automation • IT and Informatics • Genomic Information System for Integrated Sciences(GenISIS) • Pharmacogenomics Laboratory (PAL) • Established in 2007

10. Pharmacogenomics Analysis Laboratory (PAL) • CLIA88 approved laboratory with capacity to conduct medium to high throughput genotyping and gene expression assays. • Support ongoing and future pharmacogenomics observational studies and clinical trials. • Improving treatment of most illnesses by reducing toxicity and increasing efficacy of drugs by facilitating optimal treatment selection, appropriate dose individualization, and drug discovery.

11. PAL Organizational FlowChart DIRECTOR Steven A. Schichman, M.D., Ph.D. Weleetka Carter, Maria Winters, Angie Stone Dr. Steven A. Schichman PAL Director

12. Gene Expression RNA Purification & Quantification ABI Taqman, Illumina iScan & BeadXpress miRNA miRNA PAL NanoDrop UV/Vis, Agilent Bioanalyzer, Biotek Plate Reader (RiboGreen Fluorescence) TaqMan RNAse P ABI Taqman SNP Genotyping Data Analysis & Final Reports DNA Purification & Quantification ABI Taqman, Illumina iScan & BeadXpress Copy Number, EpiGenetic Events NanoDrop UV/Vis, Agilent Bioanalyzer, Biotek Plate Reader (PicoGreen Fluorescence) TaqMan RNAse P CAVHS ABI Taqman, Illumina iScan & BeadXpress Protein Quantification Protein Analysis NanoDrop UV/Vis, Agilent Bioanalyzer IlluminaBeadXpress

13. ABI 7900HT TaqMan System The ABI 7900HT (Applied Biosystems, Inc., Foster City, CA) is a PCR-based, real-time thermal cycling instrument with fluorescence detection for low-to-moderate throughput genotyping and gene expression

14. Applications Supported by ABI7900HT TaqMan Genotyping by Allelic Discrimination Real-Time Quantification Copy Number Variation Gene Expression

15. Illumina iScan System • iScan microarray scanner (Illumina, Inc., San Diego, CA) is a confocal laser scanner with dual fluorescent channels for imaging Illumina’s array-based genetic analysis products. • Automation with the AutoLoader2 provides high-throughput scanning.

16. iScan Applications BeadChip Genotyping Array: Whole-Genome SNP Analyses, Cytogenetic Analysis, Linkage Profiling Copy Number Variation: Discovery and Analysis Whole-Genome Expression Profiling, Differ- ential Gene Expression, microRNA profiling Whole-Genome Methylation Analyses, Differential Methylation, Dendrograms (Cluster Analysis)

17. IlluminaiScan Array Products

18. Illumina BeadXpress System Illumina’s BeadXpress Reader is a dual-color laser detection system for custom low- to mid-plex genotyping, methylation analysis, SNP detection and protein screening.

19. ADME Core Panel for Pharmacogenetic Genotyping • Investigate genetic associations to drug • Response • Dosing • Safety • Personalized Medicine *Absorption, Distribution, Metabolism, and Excretion

20. VeraCode ADME Core Panel • >95% Pharma ADME Core List: www.pharmaadme.org

21. IT Requirements • Large capacity Terabyte Servers • 64-Bit Computers • GenomeStudio Software Suite • Statistical Discovery Software

22. CSP Study Update • CSP 500b: Genetic Epidemiology of Amyotrophic • Lateral Sclerosis (ALS) • GWAS analysis by Affymetrix & Illumina platforms completed • 1200 ALS patients ; 400 Controls • Analysis of data ongoing at the Durham VA and Duke University Principal Investigators in CSP500b: Durham VAMC and Duke University Medical Center, NC Eugene Z. Oddone, M.D., M.H.S. Silke Schmidt, Ph.D. Dawn Provenzale, M.D., M.S. Michael A. Hauser, Ph.D. Boston MAVERIC and Tissue Core Biorepository, MA Mary Brophy, M.D. Donald E. Humphries, Ph.D. Durham VA Medical Center North Carolina

23. Summary • PAL serves as a national VA resource for various molecular, genetic and genomic analyses (low to high throughput) • Isolation to data analysis • CLIA certified