Transcript Integrating Genomics into Clinical Practice Janice S. Dorman, PhD University of Pittsburgh School of Nursing.

Integrating Genomics
into Clinical Practice
Janice S. Dorman, PhD
University of Pittsburgh
School of Nursing
Applications of Genomics to
Clinical Practice

Prediction of a healthy person’s 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
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?
Challenges Facing Clinical
Practice in the Genomics Era

Where should a clinician begin?
“Even when an individual’s 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 278:235. 1997
Why start with a family history?
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?
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
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
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
– Nursing
– Public Health
- Dentistry
- Psychology
- Social workers
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
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
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
Collecting Family History
Information in Clinical Practice
 Other
barriers?
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
Family
History
Tools
in the
Popular
Literature
US Surgeon General’s Family
History Initiative

National Family History Day,Thanksgiving,

US Partners
11/25/2004
– 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?)
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

‘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
Familial Risk Classification

Based on risk algorithm

Risk level determined mainly by

Modeled after ‘Health Family Tree
Program’ Family History Score,
University of Utah
– Number and closeness of affected
relatives
– Their ages at disease onset
– Compare observed family data to
expected based on age, gender and
race-specific incidence data
Familial Risk Classification
Average
Family
Healthware
Above
Average
Much Above
Average
Standard Public
Health Prevention
Recommendations
Personalized
Prevention
Recommendations
Personalized
Prevention
Recommendations
and Referral for
Genetic Evaluation
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?
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
Evaluation Framework
Effective
Intervention
(Benefit)
Natural
History
Quality
Assurance
Clinical
Sensitivity Prevalence
Clinical
Specificity
Ethical, Legal, &
Social Implications
(safeguards& impediments)
Pilot
Trials
PPV
NPV
Disorder
&
Setting
Penetrance
Analytic
Assay
Sensitivity
Robustness
Analytic Quality
Specificity Control
Monitoring
&
Evaluation
Education
Facilities
Health
Risks
Economic
Evaluation
Evaluation Framework

Analytical validity

Clinical validity

Clinical utility

ELSI implications
– How well does the tool identify
affected relatives?
– How well does the tool predict
disease?
– How useful is the FH tool prevent
disease?
– What are the negative aspects of
using the FH tool to identify high risk
individuals / families?
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?
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?
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

Referral to a specialist for assessment
of genetic risk factors
– Aspirin
Lipoprotein Genes Known to
Contribute to CAD Risk
Gene
Chr
Function
Gene
Apo A-I
11q
HLD component
Apo E
Apo A-IV
11q
HLD component
Apo A-II
Apo C-III
11q
Alleles assoc w
hypertriglyceridemia
Apo B
2p
Apo D
Chr
19q
Function
Ligand for LDL
receptor
1p
HLD component
LDLR
19q
Uptake of LDL
Ligand for LDL
receptor
Lp (a)
6q
Cholesterol
transport
2p
HLD component
LPL
8p
Hydrolysis of Lp lipids
Apo C-I
19q
LCAT activation
LCAT
16q
Cholesterol
esterification
Apo C-II
19q
Lp lipase activation
CETP
16q
Transfer choles
esters & phospholipids
b/w Lp
Genomic Profiling

After reviewing Mr. C’s (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)?
Genomic Profiling

Direct to physician / consumer marketing

Combination of gene variants screed is
considered proprietary and are usually not
disclosed on their websites or advertisements
– Genovations - http://www.genovations.com
– Gene Link: Genetic Biosciences for Improving the
Quality of Life - http://www.bankdna.com
– Sciona – http://www.sciona.com
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–
–
–
–
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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