Integrating Genomics into

Clinical Practice

Janice S. Dorman, PhDUniversity 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?

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?

Challenges Facing Clinical Practice in the Genomics Era

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 PracticeBarriers

– 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 - Dentistry– Nursing - Psychology– Public Health - 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 RecommendationsKnowledge

– 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

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

Collecting Family History Information in Clinical Practice

Popular Literature

Family HistoryTools in the

US Surgeon General’s 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?)

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– 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

Familial Risk Classification

Family Healthware

Much Above Average

Above Average

Average

Personalized Prevention Recommendations and Referral for Genetic Evaluation

Personalized Prevention Recommendations

Standard Public Health Prevention Recommendations

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

Effective Intervention(Benefit)

NaturalHistory

EconomicEvaluation

QualityAssurance

Education Facilities

PilotTrials

Monitoring&

Evaluation

Ethical, Legal, &Social Implications

(safeguards& impediments)HealthRisks

ClinicalSpecificity

ClinicalSensitivity Prevalence

PPVNPV

Penetrance

Assay Robustness

QualityControl

AnalyticSpecificity

AnalyticSensitivity

Disorder&

Setting

Evaluation Framework

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?

Understudied: Clinical UtilityWill 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– Aspirin

Referral to a specialist for assessment of genetic risk factors

Lipoprotein Genes Known to Contribute to CAD Risk

Gene Chr

Function Gene Chr

Function

Apo A-I 11q HLD component Apo E 19q Ligand for LDL receptor

Apo A-IV 11q HLD component Apo A-II 1p HLD component

Apo C-III 11q Alleles assoc w hypertriglyceridemia

LDLR 19q Uptake of LDL

Apo B 2p Ligand for LDL receptor

Lp (a) 6q Cholesterol transport

Apo D 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

– 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