Q: A patient with a strong family history of colon cancer is tested for Lynch syndrome. The test has a sensitivity of 99% and a false positive rate of 0.5%. If the prior probability that the patient has a mutation is 50%, what is the probability that a positive test result indicates a true mutation?

$$\displaystyle \frac{0.5 \times 1}{0.5 \times 1 + 0.5 \times 0.005} = \frac{0.5}{0.5025} \approx 99.5\%$$

Question 1

Which of the following best describes the main difference between population-level genetic screening and clinical-based genetic testing?

Accepted Answer

Population-level screening is intended to identify individuals at increased risk in the general population, while clinical-based testing is targeted at individuals with symptoms or a strong family history.

Question 2

The CDC has identified three 'tier one' genetic disorders for potential population-level screening. Which of the following is NOT one of these disorders?

Accepted Answer

Cystic fibrosis

Question 3

A genetic test for a rare mutation has a sensitivity of 99% and a false positive rate of 5%. If the prevalence of the mutation is 1 in 1000, what is the approximate probability that a person who tests positive actually has the mutation?

Accepted Answer

$$\displaystyle \frac{1}{1000} \div \left( \frac{1}{1000} + 0.05 \right) \approx 2\%$$

Question 4

Why is the positive predictive value (PPV) of a genetic test generally lower in population-level screening compared to clinical-based testing?

Accepted Answer

Because the prevalence of the disorder is lower in the general population, leading to more false positives relative to true positives.

Question 5

Which of the following statements about the ACMG list of secondary findings is TRUE?

Accepted Answer

The ACMG list is offered as an option to patients undergoing broad genetic testing, such as whole exome sequencing, regardless of their presenting symptoms.

Question 6

A patient with a strong family history of colon cancer is tested for Lynch syndrome. The test has a sensitivity of 99% and a false positive rate of 0.5%. If the prior probability that the patient has a mutation is 50%, what is the probability that a positive test result indicates a true mutation?

Accepted Answer

$$\displaystyle \frac{0.5 	imes 1}{0.5 	imes 1 + 0.5 	imes 0.005} = \frac{0.5}{0.5025} \approx 99.5\%$$

Question 7

Which of the following best explains why familial hypercholesterolemia is included as a CDC tier one disorder for population screening?

Accepted Answer

It is a genetic disorder with extremely high cholesterol levels that require early and multifaceted intervention beyond lifestyle changes.

Question 8

If a genetic test for a condition with a prevalence of 1 in 100 has a false positive rate of 0.5%, what is the approximate probability that a person who tests positive actually has the condition?

Accepted Answer

$$\displaystyle \frac{0.01}{0.01 + 0.005} = \frac{0.01}{0.015} \approx 67\%$$

Question 9

Which of the following is a key reason why population-level genetic screening is not routinely performed for most genetic disorders?

Accepted Answer

The positive predictive value of tests is often low due to the rarity of many conditions, leading to a high proportion of false positives.

Question 10

A newborn screening test is positive for a rare recessive disorder. The test has a 99% sensitivity and a 5% false positive rate. The disorder occurs in 1 in 1000 newborns. What is the most appropriate next step?

Accepted Answer

Order confirmatory diagnostic testing to determine if the child truly has the disorder.

Question 11

Which of the following best describes the concept of 'secondary findings' in the context of whole exome or genome sequencing?

Accepted Answer

Findings that are unrelated to the reason for testing but may have significant health implications for the patient.

Question 12

Which of the following equations correctly represents the calculation for the positive predictive value (PPV) of a genetic test?

Accepted Answer

$$\displaystyle 	ext{PPV} = \frac{	ext{Prevalence} 	imes 	ext{Sensitivity}}{	ext{Prevalence} 	imes 	ext{Sensitivity} + (1 - 	ext{Prevalence}) 	imes 	ext{False Positive Rate}}$$

Question 13

A direct-to-consumer genetic test advertises a 99% sensitivity and a 1% false positive rate for a rare cancer gene. Why might a positive result from this test be misleading for a healthy individual with no family history?

Accepted Answer

Because the low prevalence of the mutation in the general population means that most positive results will be false positives.

Question 14

Which of the following is a potential ethical consideration when offering secondary findings from whole exome sequencing to patients?

Accepted Answer

Some patients may not want to know about increased risks for adult-onset conditions unrelated to their current health concerns.

Question 15

In the context of genetic testing, what is the main purpose of population-level screening?

Accepted Answer

To identify individuals at increased risk who may benefit from further diagnostic evaluation or intervention.

Question 16

A test for a genetic disorder has a sensitivity of 99% and a false positive rate of 0.5%. The disorder is present in 1 in 1000 people. What is the probability that a person who tests positive actually has the disorder?

Accepted Answer

$$\displaystyle \frac{0.001}{0.001 + 0.005} = \frac{0.001}{0.006} \approx 17\%$$

Question 17

Which of the following best explains why the prevalence of a disorder in the population affects the positive predictive value of a genetic test?

Accepted Answer

Lower prevalence increases the proportion of false positives among those who test positive, reducing the positive predictive value.

Population-Level Genetic Screening: Principles, Disorders, and Test Accuracy

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