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The Power of Positive Predictive Value

Patty Taneja, MS, LCGC
| Mar 03, 2016

The verifi® noninvasive prenatal test (NIPT) has been available through Illumina’s CAP-accredited CLIA certified clinical lab in Redwood City, CA since February 2012.  In this relatively short time, the field of NIPT has shown rapid expansion. There exists a plethora of published data on various aspects of the testing, including clinical validation data, initial laboratory clinical experiences, and site-specific experiences.1-12 Professional societies have published statements supporting the use of NIPT and recommend continued test performance monitoring.13-17 More recently, there has been a shift in publications towards providing clinicians with pre- and post-test counseling tools to help them keep pace with changes, and to help ensure appropriate patient care for those electing NIPT.

In follow-up to Illumina’s first published clinical experience paper (Futch et al, June 20135), a recently published study18 highlights continued efforts to provide clinically relevant metrics for chromosomes 21, 18, and 13, evaluate any changes in the clinical population electing NIPT, and provide clinically relevant information for appropriate patient counseling.13 This study18, which includes over 86,000 clinical samples, demonstrated some important demographic changes observed since the Futch et al5 study.  First, more patients are undergoing testing in the first trimester (p<0.0001). Second, lower test positive rate were observed for chromosomes 21 and 18 (p<0.0001). Additionally, test modifications implemented in the CLIA laboratory since the Futch et al5 study have facilitated significant improvements in key performance indicators.18 These include a refinement in borderline result classification, reducing aneuploidy suspected cases to 0.3% from 2.6%5 (p<0.0001); a significant reduction in turn-around times, now 3.3 business days; and a lower technical cancellation rate, 0.1% compared with 0.7%5 previously (p<0.0001).  Observed sensitivity and specificity were calculated for this clinical population, which showed that in a clinical setting, verifi is performing as well as, or better than, early validation studies. The observed sensitivities and specificities were used to calculate positive predictive values (PPVs) based on maternal age as an a priori risk. This published PPV chart can be used as a post-test counseling tool for clinicians. 

 So what do these changes mean? How do clinicians best use the PPV tool?   What other clinical considerations need to be taken into account? Click here to listen to Patty Taneja, MS, LCGC, lead author of this publication, go through these key points and address your questions.


1. Norton ME, Brar H, Weiss J, et al. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;207(2):137.e1-8.

2. Palomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med 2012;14(3):296-305.

3. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13(11):913-20.

4. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012;119(5):890-901.

5. Futch T, Spinosa J, Bhatt S, et al. Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diagn 2013;33(6):569-74.

6. Bianchi DW, Parsa S, Bhatt S, et al. Fetal sex chromosome testing by maternal plasma DNA sequencing: Clinical laboratory experience and biology. Obstet Gynecol 2015;125(2):375-82.

7. Dar P, Curnow KJ, Gross SJ, et al. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based non-invasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211(5):527.e1–17.

8. McCullough RM, Almasri EA, Guan X, et al. Non-invasive prenatal chromosomal aneuploidy testing--clinical experience: 100,000 clinical samples. PLoS One 2014;9(10):e109173.

9. Beamon CJ, Hardisty EE, Harris SC, et al. A single center's experience with noninvasive prenatal testing. Genet Med 2014;16(9):681–7.

10. Fairbrother G, Johnson S, Musci TJ, et al. Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population. Prenat Diagn 2013;33(6):580-3.

11. Wang JC, Sahoo T, Schonberg S, et al. Discordant noninvasive prenatal testing and cytogenetic results: a study of 109 consecutive cases. Genet Med 2014;17(3):234-6.

12. Willems PJ, Dierickx H, Vandenakker E, et al. The first 3,000 Non-Invasive Prenatal Tests (NIPT) with the Harmony test in Belgium and the Netherlands. Facts Views Vis Obgyn 2014;6(1):7-12.

13. Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors. Journal of Genetic Counseling 2013;22(3):291-5.

14. Gregg AR, Gross SJ, Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med 2013;15(5):395-8.

15. Soothill PW, Lo YMD. Scientific Impact Paper No. 15: Non-invasive prenatal testing for chromosomal abnormality using maternal Plasma DNA. Royal College of Obstetricians and Gynaecologists 2014:1-14.

16. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol 2015;126(3):e31-7.

17. Benn P, Borrell A, Chiu RW, et al. Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 2015.

18. Taneja PA, Snyder HL, de Feo E, et al. Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85,000 cases. Prenat Diagn. 2015;doi:10.1002/pd.4766.