# Presentation: 326671

## Advances in Pharmacogenomics and Population-based Identification of "At-Risk" Groups

**Robert L. Davis, MD, MPH**
**Visiting Scientist**
**Immunization Safety Office**
**Centers for Disease Control and Prevention**
**Senior Investigator**
**Center for Health Studies**
**Group Health Cooperative**
**Seattle, Washington**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**Goals:**
**To understand the genetic variations that predispose children, adolescents or adults to vaccine adverse events or vaccine failure**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**The prototypic study approach:**
**Design type: Case-control study (rare outcome)**
**Case definition (example): Seizures following MMR vaccination**
**Control definition (ex): Children vaccinated with MMR who did not experience seizures**
**Assess genetic differences between cases and controls, using either ‘candidate’ genes or ‘whole genome’ approach**
**Optimally: identify a single polymorphism or group of polymorphisms very common in cases, uncommon in controls**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**The prototypic study application:**
**If able to identify a single polymorphism or group of polymorphisms very common in cases yet uncommon in controls (ie high RR for disease):**
**Assess predictive power of polymorphism(s) when applied to population**
**	****How many people need to be identified & excluded from vaccination to prevent one ****	****seizure?**
**Quantify risks and benefits of excluding children/adults from vaccination**
**	****May be different depending on vaccine, outcome, likelihood of exp to wild type disease, ****	****presence of herd immunity, etc**
**	****	****Ex: MMR and seizures**
**	****	****       ****Smallpox vaccine and myocarditis**
**Study/identify risk minimization processes**
**	****Ex: tylenol to prevent febrile seizures; vaccinating at different ages; **
**	****       ****not vaccinating, etc**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Efficiencies**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Efficiencies**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**System needs****:**
**Need to ascertain rare events after vaccination **
**	****On the order of 1/1000 to 1/10,000 (or even rarer)**
**Cannot be done with premarketing or even postmarketing clinical trials**
**Option 1: VAERS (Vaccine Adverse Events Reporting System)**
**	****	****	****Passively reported VAE**
**	****	****	**
**Option 2: Population based setting**
**	****	****	****Active identification of VAEs possible**
**	****	****	****Adv: ****	****full spectrum of VAE**
**	****	****	****	****	****unbiased ascertainment**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Systems: ****Vaccine Safety Datalink**
- Began in 1991 as a collaborative project between CDC and four HMOs:
- 	Group Health Cooperative, Seattle, WA
- 	Northwest Kaiser Permanente, Portland, OR
- 	Northern California Kaiser Permanente, Oakland
- 	South California Kaiser Permanente, Los Angeles
- Expanded in 2000 to include four more HMOs:
- 	Harvard Pilgrim Health Care, Boston, MA
- 	HealthPartners, Minneapolis, MN
- 	Kaiser Permanente Colorado, Denver, CO
- 	Marshfield Clinic, Marshfield, WI
- Total over 10 million members

## Vaccine Safety Datalink (VSD)

- Vaccination
- Records

- Health
- Outcomes
- (Hospital)
- (ER)
- (Clinic)

- Patient
- Characteristics
- (Birth records)
- (Census)

- VSD Linked
- Analysis Database

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Other: Efficiencies**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**Basic science background**
**Understanding of pathways involved in potential VAEs**
**	****Basic disease pathogenesis**
**	****Inflammation pathways**
**	****Immune response pathways**
**Used to identify potential candidate genes and candidate gene pathways**
**For many (if not most) of VAEs, this is currently unknown **
**Distinct from medication AE related (for ex) to cyp450 pathway**
**	**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Other: Efficiencies**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**Technology**
**Analytic capability**
**Technology:**
**	****Use of 500K chips for SNP analysis becoming more routine**
**	****Could partner with producers of chips (Affy; Illumina etc) for cost, individualized ****	****production etc**
**Specimen collection: typically blood samples – (buccal swabs or other in future offer possibility of ‘remote’/streamlined collection of specimens from case/family) **
**Data tracking  one of major challenges of Human Genome Project**
**	****Will need attention in any future endeavors for vaccine genomics**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**Technology**
**Analytic capability**
**500K chips give information on 500,000 single nucleotide polymorphisms**
**Challenges:**
**	****‘****typical’ logistic regression analysis has 10-100 covariates (not 500K)**
**	**
**	****1. Running chips is a specialized ‘knowledge/capability’**
**	****2. Need mainframe computers for data storage and analysis**
**	****3. Need advanced/new biostatistical algorithms for fitting models**
**	****4. Almost guaranteed to find more false than true positives**
**	****5. Individual SNPs might not be as important or illuminating as haplotypes**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**Needs:**
**Analytic capability**
**	****1. Running chips is a specialized ‘knowledge/skill’**
**	****2. Need mainframe computers for data storage and analysis**
**Need to create this capability (ie within CDC) or collaborate with academic partners**
**	****3. Need advanced/new biostatistical algorithms for fitting models**
**Needs specialized training in biostatistical genetics and genetic epidemiology**
**	**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**Needs:**
**Analytic capability**
**	****4. Almost guaranteed to find more false than true positives**
**	**
**For candidate genes: can use standard approach**
**For non-candidate genes: **
**	****(a) assess strength and consistency of association; **
**	****(b) assess biologic plausibility (if possible)**
**	****(c) replicate, replicate, replicate**
**	****5. Individual SNPs might not be as important or illuminating as haplotypes**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Other: Efficiencies**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**For identification of cases, selection of controls, and enrollment **
**	****Knowledge of vaccine/schedule/adverse events**
**	****Collaborative network with organizations/populations of interest**
**	****Historically: infectious disease specialists; epidemiologists**
**For basic science/gene pathways:**
**	****Immunologists/infectious disease specialists**
**	****Geneticists**
**For analysis:**
**	****Collaboration with partners with capabilities to run samples**
**	****Biostatisticians/genetic epidemiologists to analyze data**
**	**
**	**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Other: Efficiencies**

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**Needs:**
**Efficiencies**
**Consider moving away from specific control groups. **
**Option: genotype 1000 people from each HMO and use that as a standard control group for every study**
**Expensive to begin with, but saves cost savings and more efficient in the long run **

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**Vision for the Future:**
**Screen VSD data-sets yearly ****	****	****	****	**
**	****Identify subjects/collect specimens on cases**
**	****	****q yr: febrile seizures; severe limb swelling**
**	****	****q 5 yrs: arthritis; prolonged crying; **
**	****	****q 10 yrs: encephalopathy; GBS; anaphylaxis**
**	****	****w/high profile situations: ie intussusception;GBS**
**Run genome-scans (500K chips or higher) on cases **
**	****Compare with standard age, HMO, race matched controls**
**	**
** **

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**Vision for the Future:**
**Screen VSD data-sets yearly ****	****	****	****	**
**	****Identify subjects/collect specimens on cases**
**	****	****q yr: febrile seizures; severe limb swelling**
**	****	****q 5 yrs: arthritis; prolonged crying; **
**	****	****q 10 yrs: encephalopathy; GBS; anaphylaxis**
**	****	****w/high profile situations: ie intussusception;GBS**
**Run genome-scans (500K chips or higher) on cases **
**	****Compare with standard age, HMO, race matched controls**
**	**
**Assess findings for _candidate_ genes**
**Generate new set(s) of potential candidate genes/pathways for next iteration**
** **
** **

## Advances in Pharmacogenomics and Population-based 
Identification of "At-Risk" Groups

**Identification of "At-Risk" Groups**

**How do we create the system necessary for the optimal scientific study?**
**Presently:**
**System****: exists in integrated fashion (VSD)**
**Basic science background/scientific expertise****: needs concentration/integration**
**Technology/Analytic capability****: available; needs coordinated approach**
**Efficiencies****: needs evaluation**

## VSD Study Types

- Age specific
- Children
- Seizures (primarily febrile) after DTP and MMR
- Adolescents
- Safety of new meningococcal conjugate vaccine
- Adults
- Autoimmune thyroid disease
- Multiple sclerosis after hepatitis B
- Elderly
- Flu vaccine safety and efficacy

## VSD Data management

_**Source Data: **_**	****	****	****	****	**_**Data Center:**_
- 	Vaccination 					SAS programs
- 	Health outcomes/disease
- 	Patient characteristics
_**Analytic data file**_
- 	Highly controlled process
- 	Standardized data collection from each site
- 	Confidential and deidentified
- 	HIPAA compliant/Minimal data transfer