Objective

Noninvasive prenatal testing (NIPT), based on isolation of cell-free fetal DNA from maternal blood, is a highly efficient screening test for trisomies 21, 18, and 13. Guidelines recommend reserving the test for pregnancies with increased aneuploidy risk. Patients should receive pretest counseling by trained individuals, while screen-positive women should be referred for genetic counseling and offered invasive prenatal diagnosis. However, laboratories often report NIPT results as dichotomous (positive or negative) or trichotomous (aneuploidy detected, aneuploidy suspected, or aneuploidy not detected) outcomes, implying a degree of certainty reserved for diagnostic tests. These approaches may foster misperceptions among patients and clinicians regarding the meaning of test results and contrast maternal serum analyte-based screens, which provide individualized quantitative posttest trisomy risks. These values are useful for counseling patients in the context of their pretest trisomy risks and risks associated with invasive prenatal diagnosis. The question following a positive or negative NIPT, “What is the chance that this pregnancy is/is not affected by trisomy 21/18/13?” may be answered by the test’s positive predictive value (PPV) and negative predictive value (NPV), respectively. The PPV and NPV depend not only on the test’s sensitivity, but the prevalence, or pretest risk, of the trisomy in question. The clinical importance of these screening test characteristics, while often neglected, cannot be overemphasized. The purpose of this study was to generate post-NIPT PPVs and NPVs for a range of pretest trisomy 21, 18, and 13 risks for counseling patients and educating providers.

Study Design

Hypothetical populations of 1,000,000 subjects were assigned pretest trisomy risks ranging from 1/10–1/10,000. This range encompassed most clinically encountered pretest risks, such as those related to maternal age or resulting from serum-based screening.

Risks were stratified in increments of 1/10 from 1/10-1/100, increments of 1/50 from 1/100-1/1000, and increments of 1/250 from 1/1000-1/10,000. Respective sensitivities and false-positive rates from a recent metaanalysis for trisomies 21 (99% and 0.08%), 18 (96.8% and 0.15%), and 13 (92.1% and 0.2%) were applied to each risk stratum for each trisomy. Post-NIPT PPV and NPV were generated for each trisomy at each risk stratum.

Study Design

Hypothetical populations of 1,000,000 subjects were assigned pretest trisomy risks ranging from 1/10–1/10,000. This range encompassed most clinically encountered pretest risks, such as those related to maternal age or resulting from serum-based screening.

Risks were stratified in increments of 1/10 from 1/10-1/100, increments of 1/50 from 1/100-1/1000, and increments of 1/250 from 1/1000-1/10,000. Respective sensitivities and false-positive rates from a recent metaanalysis for trisomies 21 (99% and 0.08%), 18 (96.8% and 0.15%), and 13 (92.1% and 0.2%) were applied to each risk stratum for each trisomy. Post-NIPT PPV and NPV were generated for each trisomy at each risk stratum.

Results

Posttest PPVs for trisomies 21, 18, and 13 based on pretest risk are presented in the Table . PPVs for trisomy 21 risks ranged from 99% for pretest risks ≥1/10 to 11% for pretest risks ≤1/9750. Posttest PPVs for trisomy 18 ranged from 99% for pretest risks ≥1/10 to 6.0% for pretest risks ≤1/9500. Posttest PPVs for trisomy 13 ranged from 98% for pretest risks ≥1/10 to 4% for pretest risks equal to 1/10,000. For all trisomies and all risk strata, the NPV was ≥99%.

Table

Posttest positive predictive value following noninvasive prenatal testing

Pretest risk	Posttest PPV
1 in	Trisomy 21	Trisomy 18	Trisomy 13
10	0.99	0.99	0.98
20	0.98	0.97	0.96
30	0.98	0.96	0.94
40	0.97	0.94	0.92
50	0.96	0.93	0.90
60	0.95	0.92	0.89
70	0.95	0.90	0.87
80	0.94	0.89	0.85
90	0.93	0.88	0.84
100	0.93	0.87	0.82
150	0.89	0.81	0.76
200	0.86	0.76	0.70
250	0.83	0.72	0.65
300	0.81	0.68	0.61
350	0.78	0.65	0.57
400	0.76	0.62	0.54
450	0.73	0.59	0.51
500	0.71	0.56	0.48
550	0.69	0.54	0.46
600	0.67	0.52	0.43
650	0.66	0.50	0.42
700	0.64	0.48	0.40
750	0.62	0.46	0.38
800	0.61	0.45	0.37
850	0.59	0.43	0.35
900	0.58	0.42	0.34
950	0.57	0.40	0.33
1000	0.55	0.39	0.32
1250	0.50	0.34	0.27
1500	0.45	0.30	0.24
1750	0.41	0.27	0.21
2000	0.38	0.24	0.19
2250	0.35	0.22	0.17
2500	0.33	0.21	0.16
2750	0.31	0.19	0.14
3000	0.29	0.18	0.13
3250	0.28	0.17	0.12
3500	0.26	0.16	0.12
3750	0.25	0.15	0.11
4000	0.24	0.14	0.10
4250	0.23	0.13	0.10
4500	0.22	0.13	0.09
4750	0.21	0.12	0.09
5000	0.20	0.11	0.08
5250	0.19	0.11	0.08
5500	0.18	0.11	0.08
5750	0.18	0.10	0.07
6000	0.17	0.10	0.07
6250	0.17	0.09	0.07
6500	0.16	0.09	0.07
6750	0.15	0.09	0.06
7000	0.15	0.08	0.06
7250	0.15	0.08	0.06
7500	0.14	0.08	0.06
7750	0.14	0.08	0.06
8000	0.13	0.07	0.05
8250	0.13	0.07	0.05
8500	0.13	0.07	0.05
8750	0.12	0.07	0.05
9000	0.12	0.07	0.05
9250	0.12	0.07	0.05
9500	0.12	0.06	0.05
9750	0.11	0.06	0.05
10,000	0.11	0.06	0.04

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