Why 99% may not be as good as you think it is: limitations of screening for rare diseases

Figures & data

Table 1. Detection rates and false positive rates for trisomy 21 screening tests.

Test	Detection rate (%) (sensitivity)	False positive rate
First trimester screen [1]
NT alone	64–70%	5%
NT + serum screen	82–87%	5%
Second trimester screen [1]
Triple screen	69%	5%
Quad screen	81%	5%
First and second trimester screen [1]
Integrated (with NT)	94–96%	5%
Stepwise sequential	95%	5%
Contingent sequential	88–94%	5%
NIPT [4]	>99%	1–2%

Table 2. Test performance characteristics.

	Truth
	Disease (aneuploid)	No disease (euploid)
Test result
POSITIVE	True positive (a)	False positive (b)	a + b
NEGATIVE	False negative (c)	True negative (d)	c + d
	a + c	b + d

Sensitivity = a/(a + c), specificity = d/(b + d), PPV = a/(a + b), NPV = d/(c + d).

Table 3. Test performance characteristics in a 39-year-old woman.

	Trisomy 21
	Present (n = 1000)	Absent (n = 99 000)
Test result
POSITIVE	True positive 994	False positive 99	PPV = 994/1093 = 0.91
NEGATIVE	False negative 6	True negative 98 901	NPV = 98 901/98 907 = 1.00
	Sensitivity = 994/1000 = 0.99	Specificity = 98 010/99 000 = 0.99

Prevalence of trisomy 21 in a 39-year-old woman at 16 weeks gestation = 1:100 [5]. PPV, positive predictive value; NPV, negative predictive value.

Table 4. Test performance characteristics in a 25-year-old woman.

	Trisomy 21
	Present (n = 100)	Absent (n = 99 900)
Test result
POSITIVE	True positive 99	False positive 100	PPV = 99/199 = 0.50
NEGATIVE	False negative 1	True negative 99 800	NPV = 99 800/99 801 = 1.00
	Sensitivity = 99/100 = 0.99	Specificity = 99 800/99 900 = 1.00

Prevalence of trisomy 21 in a 25-year-old woman at 16 weeks gestation = 1:1000 [5]. PPV, positive predictive value, NPV, negative predictive value.

Figure 1. PPV for trisomy 21. The PPV for trisomy 21 varies based on the prevalence of the condition, and test specificity. With sensitivity set at 99.99%, at a given specificity, the PPV is higher with a higher prevalence of trisomy 21. *Data from Snijders et al. [5].

Screening for fetal chromosome abnormalities. ACOG Practice Bulletin No. 77. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:217–28

 PubMedGoogle Scholar

Lutgendorf MA, Stoll KS, Knutzen DM, Foglia LM. Noninvasive prenatal testing: limitations and unanswered questions. Genet Med 2013;16:281–5

 PubMed Web of Science ®Google Scholar

Snijders RJ, Sundberg K, Holzgreve W, et al. Maternal age- and gestation-specific risk for trisomy 21. Ultrasound Obstet Gynecol 1999;13:167–70

 PubMed Web of Science ®Google Scholar