Integrating Genomics into Clinical Practice

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Integrating Genomics into Clinical Practice

• Janice S. Dorman, PhD
• University of Pittsburgh
• School of Nursing

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Applications of Genomics to Clinical Practice

• Prediction of a healthy persons risk of disease
• Including cancer, cardiovascular disease,
  diabetes, etc
• Analysis of patterns of gene expression for
  diagnosis
• Evaluation of responses to environmental agents
  and drugs
• Pharmacogenomics
• Molecular diagnosis of infectious diseases

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Challenges Facing Clinical Practice in the
Genomics Era

• How can we better train the current / next
  generation of clinicians to practice genomic
  medicine?
• How can increasingly complex genetic knowledge be
  made readily accessible to all practitioners when
  they need it?

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Challenges Facing Clinical Practice in the
Genomics Era

• Where should a clinician begin?
• Even when an individuals genome can be
  displayed on a personal microchip, interpreting
  that information will depend in large part, on
  the biological and environmental contexts in
  which the genome is expressed, and the family
  milieu is as good a guide as any. Pyeritz RE.
  JAMA 278235. 1997
• Why start with a family history?

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Family History

• Is an important risk factor for chronic diseases
  that reflects
• Inherited genetic susceptibility
• Shared environment risk factors (HBP, lipids)
• Cultural factors (diet)
• Common behaviors (smoking, physical activity)
• Prior to offering any genetic testing, a
  clinician needs to assess the family history of
  disease
• What genes should be tested?
• Who should be tested?

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Family History of CVD

• Cardiovascular disease at an early age at onset
  is familial
• In Utah, 8 of population have 2 first degree
  relatives with CHD (Health Family Tree Program)
• In these families, risk of CHD (before age 50
  years) is increased 3 to 6-fold
• FH identifies a group of high risk individuals
• Using a simple and inexpensive approach
• Permits personalized intervention / prevention
• Allows for the development of family-based risk
  factor modification strategies
• Some family members may benefit from a referral
  for genetic testing

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Collecting Family History Information in Clinical
Practice

• Barriers
• Underestimation of value of family history
  information
• Limited knowledge and training in human genetics
• National Coalition for Health Professional
  Education in Genetics (NCHPEG) endorsed core
  competencies for all health-care professionals in
  2000

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NCHPEG Core Competencies

• Represents minimum knowledge, skills and
  attitudes necessary for health professionals in
  all disciplines to provide patient care that
  involves awareness of genetic issues and concerns
• Medicine - Dentistry
• Nursing - Psychology
• Public Health - Social workers

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NCHPEG Core Competencies

• Appreciate limitations of his or her genetic
  expertise
• Understand the social and psychological
  implications of genetic services
• Know how and when to make a referral to a
  genetics professional

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Some NCHPEG Recommendations

• Knowledge
• Importance of family history (minimum of 3
  generations) in assessing predisposition to
  disease
• The range of genetic approaches to treatment of
  disease
• Prevention
• Pharmacogenomics
• Genetic profiling
• Resources available to assist clients seeking
  genetic information
• The indications for genetic testing and / or
  gene-based interventions

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Some NCHPEG Recommendations

• Skills
• Gather genetic FH information, including multiple
  generation pedigrees
• Identify families who would benefit from genetic
  services
• Educate individuals regarding these services, and
  their risks and benefits
• Attitudes
• Appreciate the sensitivity of genetic information
  and the need for privacy and confidentiality
• Demonstrate willingness to update genetics
  knowledge at frequent intervals

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Collecting Family History Information in Clinical
Practice

• Other barriers?

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Collecting Family History Information in Clinical
Practice

• Other barriers
• Lack of time
• Lack of reimbursement for collecting the
  information
• Concerns about insurance / employment
  discrimination
• Lack of convenient tools / software for data
  collection

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Family History Tools in the
Popular Literature
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US Surgeon Generals Family History Initiative

• National Family History Day,Thanksgiving,
  11/25/2004
• US Partners
• Office of the Surgeon General
• National Human Genome Research Institute (NHGRI)
• Centers for Disease Control and Prevention (CDC)
• Agency for Healthcare Research and Quality (AHRQ)
• Health Resources and Services Administration
  (HRSA)
• Developed tool My Family Health Portrait
• Download free at http//www.hhs.gov/family
• Focuses on several diseases (which diseases?)

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Diseases Included in My Family Health Portrait

• Substantial public health burden
• Heart disease, stroke, diabetes and cancer
  (colorectal, breast, ovarian
• Clear case definition
• High awareness of disease status among relatives
• Accurate reporting by family members
• Family history is an established risk factor
• Effective interventions for primary and secondary
  prevention

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My Family Health Portrait

• Software is called Family Healthware
• Age, gender, race / ethnicity
• Number of relatives in each category (mother,
  father, children, etc.)
• Personal history of 6 diseases, age at diagnosis
• Risk factors (e.g., BMI, diet, exercise, etc.)
• Generates report
• Pedigree drawing
• Listing of family history data entered
• Statement about the importance of sharing the
  history with health care providers

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Familial Risk Classification

• Based on risk algorithm
• Risk level determined mainly by
• Number and closeness of affected relatives
• Their ages at disease onset
• Modeled after Health Family Tree Program Family
  History Score, University of Utah
• Compare observed family data to expected based on
  age, gender and race-specific incidence data

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Familial Risk Classification
Standard Public Health Prevention Recommendations
Average
Personalized Prevention Recommendations
Family Healthware
Above Average
Personalized Prevention Recommendations
and Referral for Genetic Evaluation
Much Above Average
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Familial Risk Classification

• Simple, easily applied, inexpensive
• Use to guide and inform prevention activities
• Resource manual for health care professionals is
  under development
• Will be organized into disease-specific chapters
  that include recommended prevention interventions
  for each level of risk
• How valid is family history information?

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Validity of FH Information

• Proband recall
• Age, gender, ethnicity of proband
• Familial relationship
• Brother, sister, mother, father, etc.
• Method of data collection
• Verification of information recalled

• Reporting bias
• Age, gender, ethnicity of proband
• Number of affected relatives
• Family dynamics
• Access to health care
• Medical knowledge
• Risk perception

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Evaluation Framework
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Evaluation Framework

• Analytical validity
• How well does the tool identify affected
  relatives?
• Clinical validity
• How well does the tool predict disease?
• Clinical utility
• How useful is the FH tool prevent disease?
• ELSI implications
• What are the negative aspects of using the FH
  tool to identify high risk individuals / families?

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Understudied Clinical Utility

• Will identification of high risk families lead to
  behavior change?
• Will FH assessment permit targeted intervention?
• Is FH useful for changing behavior?
• Is the approach cost-effective?

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Understudied ELSI Implications

• Knowledge of family history may bring unexpected
  negative effects
• Is there stigma associated with being above
  average risk?
• Is there any psychological impact of risk
  labeling?
• Is there discrimination or adverse effects on
  personal and family life?
• Do family members have a duty to inform each
  other of disease (genetic) risk factors?

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Identification and Prevention for High Risk CVD
Families

• Targeted lifestyle changes such as diet, exercise
  and stopping smoking
• Screening at earlier ages, more frequently and
  with more intensive methods than might be used of
  average risk individuals
• Use of chemoprevention approaches
• Aspirin
• Referral to a specialist for assessment of
  genetic risk factors

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Lipoprotein Genes Known to Contribute to CAD Risk
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Genomic Profiling

• After reviewing Mr. Cs (age 50) FH, his
  physician notices that this father had a heart
  attack at age 59 years
• His physical exam (including ECG and treadmill
  test) were fine
• His cholesterol was a little high
• Recommended reduced-fat diet and lipid
  lowering drug
• Mr. C has heard about a new DNA test that
  provided an individual genetic profile and
  personalized recommendation for nutritional
  supplements to prevent CAD
• Should he get the test (offered through several
  web sites)?

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Genomic Profiling

• Direct to physician / consumer marketing
• Genovations - http//www.genovations.com
• Gene Link Genetic Biosciences for Improving the
  Quality of Life - http//www.bankdna.com
• Sciona http//www.sciona.com
• Combination of gene variants screed is considered
  proprietary and are usually not disclosed on
  their websites or advertisements
• CardioGenomic Profile
• DetoxiGeonmic Profile
• ImmunoGenomic Profile
• Obesity Susceptibility Profile
• Osteopenia Susceptibility Profile
• Oxidative Stress for Skin Health and Aging
  Profile
• Tissue Repair Screen and Alcohol Metabolism
  Screen