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Challenges and Opportunities of Incorporating
Genetics into MCH Studies Session
Genetics, Genomics, Epidemiology, and MCH 12th
Annual Maternal and Child Health Epidemiology
Conference, Atlanta, GA
Sonja A Rasmussen, MD, MS National Center on
Birth Defects and Developmental Disabilities,
Centers for Disease Control and
Prevention
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National Birth Defects
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

NY
MA
IA
UT
CA
NC
AR
GA
TX
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Components of NBDPS

• Case ascertainment and review
• Maternal interview
• DNA collection on infant, mother, father

Yoon et al., Public Health Rep 11632-40,
2001 Rasmussen et al., Teratology 66(4)177-84,
2002 Rasmussen et al., Birth Defects Res Part A
Clin Mol Teratol 67193-201, 2003
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Why Study Genetic Factors and 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

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Important Considerations in the
Incorporation of Genetics 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

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Selecting Source of Specimens

• Venous blood
• Buccal cells (collected by swab, cytobrush, FTA
  cards, mouthwash, saliva)
• Newborn blood spots (previously collected)

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Issues to Consider when Selecting 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

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NBDPS Source of Specimens

• Buccal cells collected by cytobrush

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Participation Rates for Interview
and Buccal Cell Collection,
NBDPS (Atlanta) 1999-2002
Crider et al., Am J Epidemiol 164805-12, 2006
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Factors Associated with Higher Participation 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 164805-12, 2006
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Informed Consent for Studies of
Genes Not Yet Identified

• Blanket consent
• Periodic re-consent

Burke and Diekema, J Pediatr 149S34-38, 2006
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Informed Consent for 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

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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

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Components of 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

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Approaches to Disclosure of Individual 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 68-17, 2006
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Reporting Genetic Results in Research Studies
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 Studies Bookman et al., Am J Med
Genet A 1401033-40, 2006
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Reporting Genetic Results in Research 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 Studies Bookman et al., Am J Med
Genet A 1401033-40, 2006
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NBDPS Plans for Genetic Factors of 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

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Reporting Results to Study Participants
Additional Issues

• Unintended information may be revealed by genetic
  studies
• Information on other family members
• Non-paternity
• Reporting individual results on children

1, 2
2, 3
1, 1
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Choosing Genes for Analysis

• Candidate genes
• Genome-wide studies

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Candidate 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 76798810, 2006
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Genome-Wide Studies

• Linkage mapping
• Genome-wide association studies

Hirschhorn and Daly, Nat Rev Genet 695-108, 2005
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Conclusions

• 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

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Acknowledgments

• Margaret Honein
• Mary Jenkins
• Cynthia Moore
• CDC and other participating IRBs
• NBDPS Investigators in AR, CA, CDC, IA, MA, NC,
  NJ, NY, TX, UT