April 5 th, 2011 FAMILY HISTORY AND THE PUBLICS HEALTH

Objectives Describe the relevance of family history to public health Name 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.

Human Chromosomes 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 History Family history reflects effects of genetic, environmental, and behavioral factors Wide variety of common conditions have a genetic basis Heart disease Diabetes Asthma Cancer Mental illness Alzheimer disease

Family History and Risk DiseaseDisease Risk Associated with Family History Coronary heart disease (CHD) Affected sibling OR=2.0 Affected parent OR=1.5 StrokeFamily history of stroke <65 y OR=2.2 for large vessel stroke, OR= 1.9 for small vessel stroke DiabetesAffected mother OR=3.4 Affected father OR= 3.5 Both parents OR=6.1 Breast cancerOne first degree relative RR=1.8 Two first degree relatives RR=2.9 Three or more first degree relatives RR=3.9 Ovarian cancerPopulation 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 Risk A positive family history can increase an individuals 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 ProbabilityPositive Predictive Value (95%/95%) Positive Predictive Value (99%/99%) 1 in 10, %0.1% 1 in 10002%9% 1 in 10016%50% 1 in 1068%92% 1 in 295%99% PPV is the chance of having the disease in question if the test is positive. It is a function of sensitivity and specificity.

AMAs 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:

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 tools My Family History Self Portrait –Surgeon General Does It Run in the Family –Genetic Alliance

Step 3. Ask General Questions Age (or year at birth) Age and cause of death for deceased relatives Ethnic background for each grandparent Relevant 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.

Genetic Epidemiology CAD Smoking Inactivity Excess calories High fat intake Obesity (may not be completely environmental) Targeted Questions: Example Coronary Artery Disease Environmental and Behavioral Risk Factors 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 metabolism Blood pressure regulation Insulin sensitivity Thrombosis Fibrinolysis Platelet function Endothelial vessel function Inflammatory response Mutations or polymorphisms in genes associated with:

Affected members Age at diagnosis Severity 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 factors Associated diseases Developing Targeted Questions and Collecting Family History Unaffected members 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 1 st and 2 nd 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 (2 nd cousins or closer) *From

Red Flags* in an Individual A medical condition and dysmorphic features Developmental delay with dysmorphic features Learning disabilities or behavioral problems Unexplained movement disorders, hypotonia or ataxia Unexplained seizures Congenital/juvenile blindness or deafness or cataracts Disproportionate short stature or proportionate short stature with dysmorphic features Unexplained infertility *From

Step 6: Finish Your Pedigree End 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 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 60, heavy smoker, one vessel occluded, obese d. 90, stroke d. 85, prostate cancer d. 75, no CAD 54, two vessels occluded, runner, low fat diet, nonsmoker d. 62, sudden MI, nonsmoker d. 85 no CAD 61 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 1 st or 2 nd degree relative affected, especially female relatives Presence 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). 1 st and or 2 nd degree relatives with related diseases

Familial Risk Stratification (Scheuner et al, 2004) Average Familial Risk No personal or family Only one affected 2 nd degree paternal relative Only one affected 2 nd degree maternal relative Moderate Familial Risk Only personal history of later onset CAD, no family history Only one 1 st degree relative with later onset CAD Only one 2 nd degree relative affected with early onset CAD Two 2 nd 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 2 nd degree relative with CAD At least one 1 st degree relative with early onset CAD At least two 1 st 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 60, heavy smoker, one vessel occluded, obese d. 90, stroke d. 85, prostate cancer d. 75, no CAD 54, two vessels occluded, runner, low fat diet, nonsmoker d. 62, sudden MI, nonsmoker d. 85 no CAD 61 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