07: Population Genetics and Screening

Question 1

What are the criteria for carrier screening?

Answer 1

• High carrier frequency in a given population
• Availability of an inexpensive test with low false positive and false negative rates
• Infrastructure for genetic counseling
• Availability of prenatal diagnosis
• Acceptance by population

Question 2

What hemoglobinopathies are common in what populations?

Answer 2

• Carrier frequency of sickle cell is:
  
  • 1/10 in AAs
  • 1/15 in Caribbean Hispanics
• Beta thalessemia: Mediterranean
• Alpha thalassemia: Asians

Question 3

What are two new screening tests for Down Syndrome?

Answer 3

1. Multiple serum marker testing
2. Sonography for nuchal translucency

Note: These are often performed as a combined test; completed prior to 13.5 weeks; 85% sensitivity, 5% false positive.

Question 4

Describe amniocentesis.

Answer 4

Removal of amniotic fluid transabdominally by syringe.

Performed 16th-20th week.

0.5% risk of miscarriage/complication.

Question 5

Describe chorionic villus sampling (CVS).

Answer 5

Biopsy from chorionic tissue.

Performed 10th-12th week.

1% risk of miscarriage.

Question 6

What is the basis of non-invasive prenatal diagnostics?

Answer 6

Isolation of fetal cells from maternal blood. Very limited amount, present in high maternal background. Also look for free fetal DNA (ffDNA), although also limited amount (3-6%).

Question 7

What is sensitivity?

Answer 7

The measure of what proportion of those with the disease are detected.

Sensitivity = True positives / All disease positives = TP/(TP+FN)

Highly sensitive tests have a low false negative rate (so if you test negative, you most likely do NOT have the disease).

High SeNsitivity helps rule OUT a disease (SNOUT).

Question 8

What is specificity?

Answer 8

The measure of the proportion of individuals without the disease who are properly detected.

Specificity = True negative / All disease negatives = TN/(TN+FP)

Highly specific tests have a low false positive rate; if your test is positive, you HAVE the disease.

SPecificity can help rule IN (diagnose) a disease (SPIN).

Question 9

What is second tier genetic testing?

Answer 9

DNA-based confirmatory tests to decrease the number of false positives.

Question 10

Are most tests to date highly specific?

Answer 10

No; false positives are common (PKU 10:1 false:true; galactosemia 50:1, CAH 100:1)

Question 11

Is it better to be highly sensitive or highly specific?

Answer 11

Highly sensitive; means you can rule out a disease with high certainty (low false negatives). Low specificity means high false positives, but this at least means followups can be done to confirm.