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A Closer Look at False Positive Noninvasive Prenatal Test (NIPT) Results

by
Patty Taneja, MS, LCGC
| Jul 21, 2016

The verifi® noninvasive prenatal test (NIPT) has been available through the Illumina CAP-accredited CLIA-certified clinical laboratory in Redwood City, CA, since February 2012. Professional societies rapidly endorsed the use of NIPT in high-risk pregnancies.1-5 However, initial policy statements did not endorse the use of NIPT in the general-risk population due to questions about accuracy and test performance in low-risk women. Dr. Diana Bianchi and colleagues carried out the Comparison of Aneuploidy Risk Evaluations (CARE) study, which was the first study to compare performance of traditional maternal serum screening (MSS) methods to NIPT in a general-risk population in the United States.6 Published in 2014, this study showed that NIPT had significantly improved false positive rates (FPRs) compared to MSS. 6 Similarly, significantly increased positive predictive values (PPVs) were noted for NIPT when compared to MSS for trisomy 21 and trisomy 18 in a general-risk population. 6

The publication of the CARE study helped open the door for consideration of NIPT for all women, regardless of a priori risk status. The American College of Obstetrics and Gynecologists (ACOG) included NIPT as an option available to all women regardless of a priori risk in its most recent practice bulletin, and continues to emphasize the importance of accurate estimation of PPV for individual patients.7 PPV counseling tools have been introduced to help health care providers and patients understand the personal risks faced by patients following NIPT.8 Some national insurance companies now offer coverage for NIPT for all pregnant women.

While attention has been on the correlation between disease prevalence and PPV, further reducing the FPR for NIPT will increase PPVs for all patients. Differences in test platforms, mosaicism, and maternal copy-number variants have all been implicated as contributors to false positive NIPT results.9 As the verifi test platform has undergone several important informatics algorithm updates since the CARE study, Chudova et al aimed to highlight further improvements in PPVs as compared to MSS in the original study population. The reanalysis of the CARE study samples has just been published in NEJM; this reanalysis found that the updated algorithm resulted in fewer FPRs compared to the original study. The reduction in FPRs led to increased PPVs for trisomies 21 and 18: 63% and 67%, respectively. The previous NIPT algorithm demonstrated PPVs of 46% and 40%, while standard biochemical screening had PPVs of 4% and 8% for trisomies 21 and 18, respectively.10 The NIPT PPV for trisomy 13 also increased, from 25% to 50%.10

Both technical and biologic reasons were suggested as causes for the false positive results in the original CARE study cohort. The NIPT informatics improvements seen in the current publication are of significant clinical value, particularly as the clinical population choosing NIPT expands to include more general-risk women.10

Have you begun offering NIPT to all your patients? Do you feel comfortable discussing PPV with your patients? Click here to listen to Patty Taneja, MS, LCGC, review this publication in more detail.

The verifi® test was developed by, and its performance characteristics were determined by Verinata Health, Inc. (VHI) a wholly owned subsidiary of Illumina, Inc. The VHI laboratory is CAP-accredited and certified under the Clinical Laboratory Improvement Amendments (CLIA) as qualified to perform high complexity clinical laboratory testing. It has not been cleared or approved by the U.S. Food and Drug Administration or other regulatory agencies.

References:

  1. Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors. J Genet Couns 2013;22(3):291–95.
  2. Gregg AR, Gross SJ, Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med 2013;15(5):395–98.
  3. Soothill PW, Lo YMD. Scientific Impact Paper No. 15: non-invasive prenatal testing for chromosomal abnormality using maternal plasma DNA. Royal Coll Obstet Gynaecol 2014;1–14.
  4. Committee Opinion No. 640. Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol 2015;126(3):e31–e7.
  5. 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;35(8):725–34.
  6. Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370(9):799–808.
  7. American College of Obstetricians and Gynecologists. Screening for fetal aneuploidy. Practice Bulletin No. 163. Obstet Gynecol. 2016; 127(5):e123-137.
  8. NIPT/Cell Free DNA Screening Predictive Value Calculator. Perinatal Quality Foundation Web site. https://www.perinatalquality.org/Vendors/NSGC/NIPT/. Accessed July 5, 2016.
  9. Snyder MW, Simmons LE, Kitzman JO, et al. Copy-Number variation and false positive prenatal aneuploidy screening results. N Engl J Med 2015;372:1639-45.
  10. Chudova DI, Sehnert AJ, Bianchi DW. Maternal Copy Number Variants in False Positive Noninvasive Prenatal Test Results. N Engl J Med. 2016;375(1):97-98.

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