9/18/2014. How has the presentation of NIPS changed in recent years? How do we make sense of the different statistical terms?

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1 It is a common misconception among patients that NIPT is diagnostic in value. These beliefs are often based on the misconceptions formed by seeing advertised testing sensitivity and specificity reported as >99-100%...it is imperative for medical professionals and their patients to understand that NIPT is still a screening tool and cannot replace the high level of accuracy seen by diagnostic testing. Meagan Smith, Kimberly M. Lewis, Alexandrea Holmes, and Jeannie Visootsak, A Case of False Negative NIPT for Down Syndrome-Lessons Learned, Case Reports in Genetics, vol. 2014, Article ID , 3 pages, doi: /2014/

2 How has the presentation of NIPS changed in recent years? How do we make sense of the different statistical terms? What should we be looking for in our review of NIPS studies? NIPD Diagnosis NIPT Testing NIPS Screening cffdna cell free FETAL DNA cfdna Cell free DNA 2

3 During Pregnancy, some of the baby s DNA crosses the placenta into the mother s bloodstream. During pregnancy, the mother's blood contains fragments of the developing baby s DNA. Because fetal cfdna traverses the blood placental barrier and enters maternal circulation, a simple maternal blood draw allows for detection of fetal chromosomal copy number while avoiding the risks of invasive procedures % accurate, simple and trusted. Near diagnostic accuracy safer, simpler test results. a noninvasive approach to provide a high degree of accuracy for select chromosome information, without the risk of miscarriage associated with an invasive procedure. Safe. Non-invasive. 99% accurate. Delivers the lowest false-positive rate of any trisomy blood test

4 I did the Harmony test and it came back positive for T18. With what I understood to be a 99%+ accuracy I had pretty much given up on this pregnancy, but decided to do the amnio and FISH test to be 100% sure before terminating. When I got the call yesterday that my test results and ultrasound were completely normal I was completely surprised - and totally overwhelmed with emotion. How can this happen? prenatal_test_or_amnio?cpg=6 my Verifi blood test came back "positive" for Trisomy Based on everything I have read, it seems like going through the CVS is in vain since the accuracy of these blood tests are 99%+ with very low false positives. my_21_-_positive_result_-_devastated 4

5 356 High Risk Cases 184 (51.7%) true positives 38 (10.7%) False positives 19 (5.3% ultrasound findings suggestive of aneuploidy 36 (10.1%) spontaneous abortion without karyotype information 22 (6.2%) terminations without karyotype confirmation 57 (16.0%) were lost to follow-up Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, Zimmermann B, Hill M, Sigurjonsson S, Ryan A, Banjevic M, Kolacki PL, Koch SW, Strom CM, Rabinowitz M, Benn P. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol Aug 8. [Epub ahead of print] Sensitivity-measures the proportion of positives which are correctly identified as positive Specificity- measures the proportion of negatives which are correctly identified as negative 5

6 Positive Predictive Value - the likelihood that a positive test is a true positive Negative Predictive Value -the likelihood that a negative test is a true negative PPV and NPV are not intrinsic to test performance depend on prevalence Down Syndrome = 1 in 250 (35 yo) DS (400) No DS (99,600) Sensitivity 99.5% Specificity 99.9% Test Positive 498 True Positive 398 False Positive 100 PPV 398/498 =.80 Test Negative 99,502 False Negative 2 True Negative 99,500 NPV 99,500/99,502 =.999 Test Positive 498 Down Syndrome = 1 in 250 (35yo) DS (400) No DS (99,600) Sensitivity 99.5% Specificity 99.9% false positive result 1 in 5 True Positive 398 False Positive 100 PPV 398/498 =.80 Test Negative 99,502 False Negative 2 True Negative 99,500 NPV 99,500/99,502 =.999 6

7 07/11/guest-post-nips-is-notdiagnostic-convincing-ourpatients-and-convincingourselves/ Aneuploidy Positive results with NIPS Confirmed with diagnostic test T /41 (93%) T /25 (64%) T /16 (44%) 45X 16 6/16 (38%) Wang JC, Sahoo T, Schonberg S, Kopita KA, Ross L, Patek K, Strom CM. Discordant noninvasive prenatal testing and cytogenetic results: a study of 109 consecutive cases. Genet Med Aug 7. Accuracy - the proportion of true results (both true positives and true negatives) in the population. 7

8 False Positive Rate- Of all women screened, the proportion who will have a positive result that is a false positive result FPR and Accuracy do not speak to the reliability of any single given test for an individual woman. It is a population metric. PPV NPV Sensitivity Specificity T T T T21 >99.9% 99.8% T % 99.6% T % >99.9% Down Syndrome Incidence - 1 in 4 DS (25,000) DS (75,000) Test Positive 25,125 Sensitivity 99.9% True Positive 24,975 Specificity 99.8% False Positive 150 PPV 24,975/25125 =.994 Test Negative 74,875 False Negative 25 True Negative 74,850 NPV 74,850/74875 =.999 8

9 Follow-up data for negative results reported? Information about no-call results included? Are all informative samples used in performance data calculations? Do study groups have artificially high incidence of aneuploidy? Sample size? Potential for industry bias? Obstet Gynecol Aug;124(2 Pt 1): The overall cohort included 1,064 samples: 926 euploid, 67 trisomy 21, 32 trisomy 18, 14 trisomy 13, 12 monosomy X, 2 47,XXY, one 47,XXX, one 47, XYY, six triploid, and three samples (one trisomy 13, two monosomy X) with confirmed fetal mosaicism. Pergament et al Obstet Gynecol Aug;124(2 Pt 1):

10 cfdna testing merits serious consideration as a primary screening method for fetal autosomal aneuploidy. N Engl J Med Feb 27;370(9): NEJM-Published study finds verify prenatal test achieved 10x higher positive predictive value vs current standard of care August 2014 Prospective, blinded study comparing NIPS to biochem screening Both methods detected all cases of true aneuploidy (5 cases of T21, 2 cases of T18, and 1 case of T13), Ages (mean 29.6) The positive predictive values of cfdna testing vs biochem T % with NIPS - 4.2% with biochemical screening T % with NIPS - 8.3% with biochemical screening Bianchi DW, Parker RL, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med Feb 27;370(9): in in in 50 >1 in 10 Biochemical NIPS Positive Aneuploidy detected >99% risk score 10

11 Genetic Counseling Pregnant? Prenatal Screening? Results Diagnostic Testing DTC Advertising OB Provider Family and Friends As with any prenatal testing, patients must have accurate, up-to date information regarding the test, the possible results, and the available follow-up in order to make an informed choice when considering NIPT due to limited resources, it may not be feasible for all women seeking NIPT to receive pretest counseling from a genetic counselor. But a qualified healthcare provider should provide nondirective pretest counseling for all women considering NIPT. diagnosis: the position of the National Society of Genetic Counselors. Noninvasive prenatal testing/noninvasive prenatal 11

12 Minkoff H, Berkowitz R. The case for universal prenatal genetic counseling. Obstet Gynecol Jun;123(6):