Risk Calculation Ethical and Legal

IssuesMPH

6-4-15

Learning Objectives

• By the end of this lecture……….we all should be able to:

– Appreciate the role of Clinical Genetics

– Explain the role of Genetics in Clinical Practice

– Calculate the probabilities of simple genetic problems

– Calculate risks of genetic diseases in given cases.

– Discuss the ethical and Legal issues related to Genetics

Clinical Genetics

Clinical Genetics is a medical specialty which provides a diagnostic services and genetic

counseling for individuals or families with, or at risk of, conditions which may have a genetic

basis.

Who is referred to Clinical Geneticisit’sClinic?

• A person with a known genetic condition in the family, wanting to know the risks.

• Parents of a child with physical and/or learning difficulties which may be due to a genetic condition, referred to see if a diagnosis can be made

• Person with a strong family history of cancer, wanting to know if they are at increased risk, and if they are, what options they have.

• A person with a known genetic condition wanting specialist advice about the condition

• A person with a possible genetic condition in the family wanting to know if a diagnosis can be made, and if so, their risks and options

• A pregnant couple told that a test has given an abnormal result, wanting to talk about what the result means, and what options are available.

Genetic Screening

Family Screening:

• Screening of individuals and couples known to be at significant or high risk because of a positive family history -sometimes referred to as targeted, or family, screening because it focuses on those most likely to benefit. – Carriers

– Heterozygote screening.

– Pre-symptomatic testing.

Genetic screeningObjectives

General screening• Low risk population.• Primary objective is to

enhance autonomy by enabling individuals to be better informed about genetic risks and reproductive options.

• Secondary goal is the prevention of morbidity due to genetic disease and alleviation of the suffering that this would impose.

Presymptomatic Diagnostic Methods

• Clinical Examination

• Specialist Investigation

• Biochemical Tests

• Linked DNA Markers

Presymptomatic Diagnosis of Neurofibromatosis ICinical Examination

• Autosomal dominant disorder neurofibromatosis type I (NF I ) can have a number of different clinical features .

• Unaffected relative of NF I pateitns can be examined for signs such as cafe-au-lait spots or cutaneous neurofibromas.NF I is a relatively rare example of a dominantly inherited disorder that is virtually l 00% penetrant by the age of 5 or 6 years, with visible external features.

Specialist Examiniation

• Similarly, assessment for Marfan syndrome involves ophthalmic examination for evidence of ectopia lentis, echocardiography for measurement of the aortic root diameter, and magnetic resonance imaging of the lumbar spine to look for evidence of dural ectasia - all of these features count as major criteria in the disorder.

Biochemical Tests

• Serum Cholesterol Level for the hypercholesterolemia

Linked DNA Markers

• The demonstration of linkage between a DNA sequence variant and a disease locus overcomes the need to identify a biochemical defect or protein marker and the necessity for it to be expressed in accessible tissues.

• In addition, use of markers at the DNA level also overcomes the difficulties that occur in carrier detection due to X-inactivation for women at risk for X-linked disorders.

Diseases where Linked DNA Markers

can be used

Risk CalculationAnatomy of a Pedigree Chart

Problem-1

In Pedigree, which of the following females is least likely to be a heterozygote for the rare X-linked recessive gene,III-1, III-3, or III-5?

Problem-2

• A patient of yours is getting married and comes to you for counseling. She has a brother with a rare X-linked recessive disease. Her mother's father also had the disease. She wants to know the probability of her being a carrier of the disease and the probability that she will pass the disease to her children.What is your advice?

Answer

• Her mother was a carrier

• She has a 50% of being a carrier, depending upon which of her mother's X chromosomes she inherited.

• If she is a carrier she will pass the affected X to her son 50% of the time.

• Her daughters will not be affected because theywill always get a normal X from their father.

Recurrencerisk

• One of the most important aspects of genetic counseling is the provision of a risk figure, called Recurrence risk.

• Estimation of the recurrence risk usually requires careful consideration and takes into account:

– The diagnosis and its mode of inheritance

– Analysis of the family pedigree

– The results of tests that can include linkage studies.

Probablity

• The probability of an outcome can be defined as the proportion of times it occurs in a large series of events.

• Conventionally, probability is indicated as a proportion of 1. – A probability of 0 implies that an outcome will never be

observed.– A probability of 1 implies that it will always be observed. – Therefore, a probability of 0.25 indicates that, on average,

a particular outcome or event will be observed on 1 in 4 occasions, or 25%.

– The probability that the outcome will not occur is 0.75, which can also be expressed as 3 chances out of 4, or 75%.

Let’s practice

Prior/Anterior Probability

• The initial probability of each event is known as its prior probability, and is based on

ancestral or anterior information.

Anterior and Posterior Probabilities

• Anterior probability of getting heads on a single toss of a penny is 1/2, since there are two equal possibilities, H or T.

• Then, given two pennies tossed at random, HH, HT, TH, and TT are all equally likely and the anterior probability of getting at least one head is 3/4.

• The anterior probability that any combination with at least one head will have two tails (HT or TH vs HH) is 2/3.

• If one penny is tossed and it shows H, What is the probability that the other is also H? The a posteriorprobability is 1/2 : given the knowledge that one coin is H, the other is H or T with equal probability.

• In analyzing the results of any particular experiment, the added information changes probabilities a posteriori.

Mutually Exclusive Events

– Law of Addition:

If the events are mutually exclusive, then the probability that either one or the other will occur equals the sum of their individual probabilities. The probability that the baby will be either a boy or a girl equals1 (1/2 + 1/2)

– Law of Multiplication:

If two or more events or outcomes are independent, then the probability that both the first and the second will occur equals the product of their individual probabilities. If the mother is found on ultrasonography to be carrying twins who are non-identical, then the probability that both the first and the second twin will be boys equals 1/4 (1/2 x 1/2).

Bayes’ TheoremApplications

• Devised by the Reverend Thomas Bayes.

• Provides a valuable method for determining the overall probability of an event or outcome.

• It considers all initial possibilities (e.g. carrier or non-carrier) and then modifies these by incorporating information, such as test results.

• It combines the probability that an event will occur with the probability that it will not occur.

Concepts

Conditional Probability

The observations that modify these prior probabilities allow conditional probabilities to

be determined.

Concepts

Posterior Information

In genetic counseling these are usually based on numbers of offspring and/ or the results of

tests.

Concepts

Joint Probability

The resulting probability for each event or outcome is known as its joint probability.

Concepts

Posterior/ Relative probability

The final probability for each event is known as its posterior or relative probability and is

obtained by dividing the joint probability for that event by the sum of all the joint

probabilities.

Worked Example

Consider a pedigree where the consultandII1 wishes to know the probability that her male fetus will have X-linked Haemophilia

Worked ExampleHistory

1. She has an unaffected son

2. She had a brother and two maternal uncles with a clinical diagnosis but no molecular testing is available

Worked Example Calculations

1. On the basis of her mother being obligate carrier, she gets a probability of ½ of being a carrier

2. Her anterior probability of not being a carrier is also ½.3. Since they are mutually exclusive events, there sum equals to 14. Her unaffected son decreases the chance of her being a career.5. The conditional probability that a career would have an unaffected son is ½P6. The conditional probability that a non-carrier will have an unaffected son is 17. The posterior probability that she is a carrier is 1/38. The posterior probability that she is not a carrier is 2/39. Since it is an X-linked condition, there is a 50% chance that she would transmit the disease

to her son if she is a carrier10. So the chance that the fetus will be affected is 1/3 x 1/2 = 1/6

GeneticsEthical & Legal Issues

Thank you!