Challenges and Opportunities Challenges and Opportunities of Incorporating of Incorporating

Genetics into MCH StudiesGenetics into MCH StudiesSession: Session: Genetics, Genomics, Genetics, Genomics,

Epidemiology, and MCHEpidemiology, and MCH 12th Annual Maternal and Child Health 12th Annual Maternal and Child Health Epidemiology Conference, Atlanta, GAEpidemiology Conference, Atlanta, GA

Sonja A Rasmussen, MD, MS

National Center on Birth Defects and Developmental Disabilities, Centers for

Disease Control and Prevention

National Birth Defects National Birth Defects Prevention Study (NBDPS) Prevention Study (NBDPS)

• Case-control study of major birth defects

• Evaluate genetic and environmental risk factors

• Enrollment began with births on or after 10/1/97

CACAUTUT

TXTX

ARARGAGA

NCNC

NYNY MAMA

IAIA

Components of NBDPS

• Case ascertainment and review

• Maternal interview

• DNA collection on infant, mother, father

Yoon et al., Public Health Rep 116:32-40, 2001Rasmussen et al., Teratology 66(4):177-84, 2002

Rasmussen et al., Birth Defects Res Part A Clin Mol Teratol 67:193-201, 2003

Why Study Genetic Factors and Why Study Genetic Factors and Gene-Environment Interaction?Gene-Environment Interaction?Why Study Genetic Factors and Why Study Genetic Factors and Gene-Environment Interaction?Gene-Environment Interaction?

• Results in improved understanding of etiology

• Allows identification of:

– populations at high risk (susceptible genotype)

– modifiable risk factors (environmental exposures)

• Increases opportunities for prevention

Important Considerations Important Considerations in the Incorporation of in the Incorporation of

Genetics into MCH StudiesGenetics into MCH Studies

Important Considerations Important Considerations in the Incorporation of in the Incorporation of

Genetics into MCH StudiesGenetics into MCH Studies

• Selecting source of specimens• Maximizing participation rates• Human subjects-related issues

– Informed consent for studies of genes not yet identified

– Disclosure of individual results• Choosing genes for analysis and

analytic approach to be used

Selecting Source of SpecimensSelecting Source of SpecimensSelecting Source of SpecimensSelecting Source of Specimens

• Venous blood

• Buccal cells (collected by swab, cytobrush, FTA® cards, mouthwash, saliva)

• Newborn blood spots (previously collected)

Issues to Consider when Issues to Consider when Selecting Source of SpecimensSelecting Source of Specimens

Issues to Consider when Issues to Consider when Selecting Source of SpecimensSelecting Source of Specimens

• Amount of DNA

• Quality of DNA

• Other possible uses of sample source

• Cost/ease of collection

• Age of participants

• Impact on participation rates

NBDPS Source of SpecimensNBDPS Source of SpecimensNBDPS Source of SpecimensNBDPS Source of Specimens

• Buccal cells collected by cytobrush

Participation Rates for Interview Participation Rates for Interview and Buccal Cell Collection, and Buccal Cell Collection,

NBDPS (Atlanta) 1999-2002 NBDPS (Atlanta) 1999-2002

78.3

70.162.9 61.0

71.9

47.640.039.1

34.9

61.1

0102030405060708090

100

Non-Hispanic

White

Non-Hispanic

Black

Hispanic Asian orPacific

Islander

Total

Pa

rtic

ipa

tio

n R

ate

Interview

Buccal cellcollection

Crider et al., Am J Epidemiol 164:805-12, 2006

Factors Associated with Higher Factors Associated with Higher Participation in Buccal Cell CollectionParticipation in Buccal Cell Collection

Factors Associated with Higher Factors Associated with Higher Participation in Buccal Cell CollectionParticipation in Buccal Cell Collection

• Non-Hispanic white race/ethnicity

• English-language (vs. Spanish) interview

• Receipt of a redesigned mailing packet and additional $20 incentive

• Consumption of folic acid

Crider et al., Am J Epidemiol 164:805-12, 2006

Informed Consent for Studies of Genes Not Yet Identified

• “Blanket” consent

• Periodic re-consent

Burke and Diekema, J Pediatr 149:S34-38, 2006

Informed Consent for Informed Consent for NBDPS Genetic Studies NBDPS Genetic Studies

• Study started in 1997 - biologics specimens to be used for decades

• Plan to study hundreds of genetic factors – some not yet discovered, methods of study likely to change

• Informed consent states that samples will be used to study genes that may play a role in birth defects causation

NBDPS “Gene One-Pager”NBDPS “Gene One-Pager”

• For each genetic factor to be studied, investigator will submit gene one-pager to CDC IRB as protocol amendment for expedited review

Components of Components of “Gene One-Pager”“Gene One-Pager”

• Proposed genetic research and justification of why testing is important

• Is this test of clinical significance?

• If yes, what additional efforts that concern human subjects protection will be made by the investigators? 

• Any other information related to this research that may be important to IRB

Approaches to Disclosure of Approaches to Disclosure of Individual Genetics ResultsIndividual Genetics Results

• Research-focused approach – results should generally not be offered because goal of research is to provide generalizable (not individual) knowledge

• Autonomy-focused approach – all results should be offered because individuals have a right to information about themselves

Ravitsky and Wilfond, Am J Bioeth 6:8-17, 2006

Reporting Genetic Results in Research Reporting Genetic Results in Research Studies: RecommendationsStudies: Recommendations

• Key criteria– Risk for disease should be significant– Disease should have important health

implications (i.e., mortality, morbidity, significant reproductive implications)

– Proven therapeutic or preventive interventions should be available

• Final decision should be made with IRB approval after careful consideration of risks and benefits

NHLBI Working Group on Reporting Genetic Results in Research StudiesBookman et al., Am J Med Genet A 140:1033-40, 2006

Reporting Genetic Results in Research Reporting Genetic Results in Research Studies: Recommendations (continued)Studies: Recommendations (continued)

• Genetic test results should not be reported to study participants and their health care providers unless test was performed in a CLIA-certified laboratory

• Counselor/consultant should be provided to explain nature of study, implications of participation, potential relevance of genetic results

• Information on what to do with results should be summarized, preferably on a single page

NHLBI Working Group on Reporting Genetic Results in Research StudiesBookman et al., Am J Med Genet A 140:1033-40, 2006

NBDPS Plans for Genetic Factors NBDPS Plans for Genetic Factors of Clinical Significanceof Clinical Significance

• Testing must be done in a CLIA-certified laboratory so results can be provided to study participants if desired

• Study participants notified of summarized results of genetic factors with clinical significance by NBDPS newsletter

• Participants can request results if desired

• Informed consent form reflects this approach

Reporting Results to Study Reporting Results to Study Participants: Additional IssuesParticipants: Additional Issues

• Unintended information may be revealed by genetic studies

– Information on other family members

– Non-paternity

• Reporting individual results on children

1, 22, 3

1, 1

Choosing Genes for AnalysisChoosing Genes for AnalysisChoosing Genes for AnalysisChoosing Genes for Analysis

• Candidate genes

• Genome-wide studies

Candidate Gene StudiesCandidate Gene StudiesCandidate Gene StudiesCandidate Gene Studies

• Candidate gene – a gene for which there is evidence of its possible role in the trait or disease that is under study– Based on previously reported

associations in epidemiologic or family studies, biologic plausibility, expression or linkage studies, and other factors

Green and Moore, Birth Defects Res Part A Clin Mol Teratol 76:798–810, 2006

Genome-Wide StudiesGenome-Wide StudiesGenome-Wide StudiesGenome-Wide Studies

• Linkage mapping

• Genome-wide association studies

Hirschhorn and Daly, Nat Rev Genet 6:95-108, 2005

ConclusionsConclusions

• Incorporating genetics into MCH studies holds promise for better understanding of disease etiology and possibly improved primary prevention

• Several considerations need to be taken into account when designing a study that incorporates genetics

AcknowledgmentsAcknowledgments

• Margaret Honein

• Mary Jenkins

• Cynthia Moore

• CDC and other participating IRBs

• NBDPS Investigators in AR, CA, CDC, IA, MA, NC, NJ, NY, TX, UT