April 5th, 2011

FAMILY HISTORY AND THE PUBLIC’S HEALTH

ObjectivesDescribe the relevance of family history to

public healthName two factors indicative of a family

history with significant genomic risks

But first… a brief review of genetics

What is a genetic condition?

A condition caused by:A change in the

usual number or structure of chromosomes.

A change in a single gene.

A change in multiple genes.

Chromosome Conditions

Single Gene Genetic Conditions

Caused by a change, called a mutation, in one gene.

People have about 30,000 genes.

We know of at least 3000 single gene conditions.

Different patterns of inheritance

Patterns of Inheritance

•Present in many generations•Child of affected parent at 50% risk

•Present in one sibship•Carrier (healthy) parents have 25% chance of affected child per pregnancy

•Looks like it skips generations since carrier females are healthy•50% risk to sons of unaffected carrier females

Multifactorial or Complex Genetic Conditions

Caused by variations multiple genes, each with a small additive effect in increasing susceptibility to developing a condition

Environmental factors also play a role

Genomic Medicine

Just learning how the rest of our genes can contribute common diseases.

In 10 years, we may all know all of our genetic traits.

This will open a whole new era of medicine.

However, until that time, family history is the best genomic

medicine tool.

Importance of Family HistoryFamily history

reflects effects of genetic, environmental, and behavioral factors

Wide variety of common conditions have a genetic basisHeart diseaseDiabetesAsthmaCancerMental illnessAlzheimer disease

Family History and RiskDisease Disease Risk Associated with Family

History

Coronary heart disease (CHD)

Affected sibling OR=2.0Affected parent OR=1.5

Stroke Family history of stroke <65 y OR=2.2 for large vessel stroke, OR= 1.9 for small vessel stroke

Diabetes Affected mother OR=3.4Affected father OR= 3.5Both parents OR=6.1

Breast cancer One first degree relative RR=1.8Two first degree relatives RR=2.9Three or more first degree relatives RR=3.9

Ovarian cancer Population risk ~1.6%First degree relative ~5%Hereditary breast ovarian cancer syndrome- up to 60%

Adapted from Yoon et al, Preventing Chronic Disease (2009)

Family History and Genetic Testing

Genetic testing is available for an increasing number of conditions.

Family history can identify people with an increased risk of specific disorders who might be best candidates for single gene genetic tests.

Also identifies who may benefit most from increased screening, lifestyle changes, and prophylactic measures whether or not genetic testing is available.

Family History and RiskA positive family history

can increase an individual’s risk of developing a given disease (pre-test probability).

Thus, using family history can help in assessing PPV of available screening tests or genetic tests.

Ultimately, this can help in the clinical management of the patient and is allocating health care dollars

Risk and Positive Predictive Value (PPV) of a Test

Prior Probability Positive Predictive Value (95%/95%)

Positive Predictive Value (99%/99%)

1 in 10,000 0.02% 0.1%

1 in 1000 2% 9%

1 in 100 16% 50%

1 in 10 68% 92%

1 in 2 95% 99%

PPV is the chance of having the disease in question if the test is positive. It is a function of sensitivity and specificity.

AMA’s Position on Family History

Early identification of families with chronic diseases through family history is beneficial.

Risk assessment for each disease is unique.Personalized prevention programs for

treatable disorders should be based on individual risk assessment.

Encourage patients to generate their own family medical history to promote a sense of responsibility and partnership in health care.

“Medical care will be changed fundamentally as advances in understanding the genetic basis of disease become incorporated into diagnosis, treatment, and prevention.”

Rich EC, Burke W, Heaton C, et al. Reconsidering the family history in primary care. J Gen Intern Med 2004;19:273-280.

Six Easy Steps to Getting Good Quality Family History Information

Step 1: Know How to Construct a Pedigree

Generally a three-four generation pedigree is ideal.

Sample Pedigree

Step 2: Prepare the Patient

Explain what you are doing and why.Explain what type of information you are

looking for.When possible, notify patients ahead of time

that you will be requesting family history information so they can prepare.

Encourage them to use existing toolsMy Family History Self Portrait –Surgeon

General https://familyhistory.hhs.gov/fhh-web/home.action

Does It Run in the Family –Genetic Alliance http://familyhealthhistory.org/

Step 3. Ask General QuestionsAge (or year at birth)Age and cause of death

for deceased relativesEthnic background for

each grandparentRelevant health

information Illnesses and AGE at

diagnosis (including contributing factors,

Severity of condition

Information regarding prior genetic testing in the family or patient

Information regarding pregnancies including infertility, SAB, stillbirths, pregnancy complications

Include information about half siblings

Ask about consanguinity

Step 4: Ask Targeted Questions

Targeted questions are those specific to the symptoms of the condition you are assessing in the family history.

Helps identify people in the family who may have been affected (unbeknownst to your patient) or may be at risk.

Also identifies related conditions that could pose increased risk.

Generate questions based on what you know about symptoms and causes of the condition.

SmokingInactivityExcess caloriesHigh fat intakeObesity (may not be

completely environmental)

Targeted Questions: Example Coronary Artery Disease

Common disorder Males: 35% risk by 70,

49% by 90 Females: 24% by 70, 32%

by 90. Average onset about 10 years later than men.

Most cases considered multifactorial Relatives of affected

women have in general a higher risk of CAD

Rarely, CAD arises due to a single gene disorder.

Genetic Risk Factors (Most Associated With Multifactorial Predisposition)

Lipid metabolismBlood pressure

regulationInsulin sensitivityThrombosis

FibrinolysisPlatelet functionEndothelial

vessel functionInflammatory

response

Mutations or polymorphisms in genes associated with:

Age at diagnosisSeverity

Degree of blockage, number of vessels occluded

Behavioral factors Smoking, diet, obesity, exercise,

medications

Biochemical risk factors Cholesterol levels, triglycerides

Associated diseases HTN, diabetes, stroke,

peripheral vascular disease, aortic aneurysm, lipid abnormalities

Age if living or age at death

Behavioral factors Biochemical risk

factorsAssociated diseases

Developing Targeted Questions and Collecting Family History

Ideally, collect information and draw a pedigree at least for all

first and second degree relatives. Document ethnicity

and consanguinity.

Step 5. Assess- Look For Red Flags*

Several 1st and 2nd degree relatives with the same or related conditions

A common disorder with earlier onset than usual, especially if occurring multiple family members

Sudden death in someone who seemed healthy

3 or more pregnancy losses in an individual/couple

Medical problems in children of parents who are closely related (2nd cousins or closer)

*From www.ama-assn.org/ama/pub/category/2380.html.

Red Flags* in an Individual

A medical condition and dysmorphic featuresDevelopmental delay with dysmorphic

featuresLearning disabilities or behavioral problemsUnexplained movement disorders, hypotonia

or ataxiaUnexplained seizuresCongenital/juvenile blindness or deafness or

cataractsDisproportionate short stature or

proportionate short stature with dysmorphic features

Unexplained infertility

*From www.ama-assn.org/ama/pub/category/2380.html.

Step 6: Finish Your PedigreeEnd with some

summary questions General questions

(anyone else with any birth defects, mental retardation, chronic health conditions that we have not discussed)

Targeted questions regarding issue at hand

You are never really finished with a family history. Dynamic, needs to be

updated regularly.

Pedigrees in Practice: Bob versus Bill

Bob Bill

MI MI

Bob and Bill are both referred to you to discuss their risk of coronary artery disease. Each has a father who had myocardial infarction related to a

blocked artery(ies). Who is at greater risk of CAD?

Targeted Family History

Bob Bill

35 35

MI @ 60, heavy smoker, one vessel occluded, obese

61

85

65

d. 90, stroke

62 55

d. 85, prostate cancer

d. 75, no CAD

MI @ 54, two vessels occluded, runner, low fat diet, nonsmoker

d. 62, sudden MI, nonsmoker

65

85

6257 57

87

d. 85 no CAD

61

English, Irish English, Irish

Assessing Risk: Red Flags for Susceptibility to CAD

Early onset CAD (men <55, women < 65)Angiographic severity (how occluded were vessels)Multiple vessels involved (e.g., coronaries, carotid,

aorta)More than one 1st or 2nd degree relative affected,

especially female relativesPresence of multiple established or emerging CAD

(newly identified) risk factors in affected relatives Absence of established risk factors in family

members with CAD (elevated total and LDL cholesterol, low HDL cholesterol, HTN, diabetes, smoking, other behavioral risk factors).

1st and or 2nd degree relatives with related diseases

Familial Risk Stratification (Scheuner et al, 2004)

Average Familial Risk No personal or family Only one affected 2nd

degree paternal relative

Only one affected 2nd degree maternal relative

Moderate Familial Risk Only personal history of later

onset CAD, no family history Only one 1st degree relative

with later onset CAD Only one 2nd degree relative

affected with early onset CAD

Two 2nd degree relatives from one lineage with late or unknown CAD onset

High Familial Risk Personal history of early onset Personal history of later onset and at least

one 2nd degree relative with CAD At least one 1st degree relative with early

onset CAD At least two 1st degree relatives with CAD at

any age

Managing Risk

High Risk

Clarify and verify family history

Pedigree analysis to assess possibility of Mendelian disorder

Clinical assessment of established and emerging risk factors every 1-2 years

Consider early detection strategies every 2-3 years, 10 years prior to earliest age of onset

Personalized prevention messages tailored to identify CAD risk factors and sub-clinical disease

Referral of relatives

Moderate Risk

Clarify and verify family history

Clinical assessment of established risk factors every 2-3 years. If multiple risk factors identified, assign high risk.

Personalized prevention messages to identify risk factors

Average Risk

Clinical assessment of established risk factors every 5 years.

Public health prevention messages.

Collect family history every 1-2 years!

Back to Bill and Bob. Who is at higher risk? How would you manage risk?

Bob Bill

35 35

MI @ 60, heavy smoker, one vessel occluded, obese

61

85

65

d. 90, stroke

62 55

d. 85, prostate cancer

d. 75, no CAD

MI @ 54, two vessels occluded, runner, low fat diet, nonsmoker

d. 62, sudden MI, nonsmoker

65

85

6257 57

87

d. 85 no CAD

61

English, Irish English, Irish

Moderate Familial Risk High Familial Risk

In conclusion…Family history is currently the best genomic

medicine tool available Two factors- early age of onset and number of

affected relatives- are good indicators of increased genomic risks

Using family history to stratify risk can determine who would benefit most from medical screening, preventive measures and/or genetic testing –PERSONALIZED MEDICINE

Risk stratification can lead to more targeted use of health care dollars