blog.illumina

  1. At Illumina, we recognize that as genetic testing becomes more commonplace and complex, the need for education will continue to grow. Journal publications, scientific conferences, news media sources, and even social media sites share updates and information about popular test options like prenatal screening. Specific testing information regarding non-invasive prenatal testing (NIPT) and marketing materials are available through the Illumina accredited clinical lab in Redwood City, California. However, individuals looking for information on prenatal screening may need to start with a basic genetics refresher before moving forward.

    As part of the ongoing effort by Illumina to provide our customers with educational support, the Reproductive and Genetic Health genetics counseling team developed a series of brief modules entitled “Noninvasive Prenatal Testing: Background, Science and Clinical Implementation.” The first two modules, “Chromosomes, DNA, and Review of Aneuploidy Syndromes” and “Overview of Screening Terminology and Available Aneuploidy Testing Options” were made available for viewing in May 2016.

    We are excited to release the next two modules:

    Module 3 entitled, “Clinical Implementation of Noninvasive Prenatal Testing”reviews key societal position statements pertaining to NIPT and addresses both pre- and post-test counseling considerations. Using case examples, this module reviews clinical considerations following positive and negative NIPT results, as well as clinical management following an NIPT failure.

    Click here to view: https://youtu.be/P2pn-dFy3r4 

    Module 4 entitled, “Challenges of Noninvasive Prenatal Testing: Discordance Etiologies, Cases & Management” addresses biological reasons for discordance between NIPT results and clinical outcome, including mosaicism, co-twin demise, maternal genetic aberrations, maternal medical conditions, and copy number variation. Real case examples are used to illustrate each of these etiologies.

    Click here to view: https://youtu.be/r4lc_FwLXXA

    These modules can be watched (and re-watched) at one’s own pace. For reference laboratories or national laboratory partners looking for more information on NIPT for their employees, to clinicians who need a quick review of available prenatal screening options, to prospective parents interested in learning more about these topics, these modules are for YOU. Stay tuned for two additional modules later this year!

  2. 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.6Published 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 studyhelped 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.
  3. It’s often said that a day makes a difference in politics. In science, a decade makes a huge difference. It is almost a decade since Mastenbroek and colleagues (1) put an end to what we now think of as a primitive form of Preimplantation Genetic Screening (PGS) with their large randomised clinical trial (RCT) targeting a handful of different chromosomes using FISH on a single cell from a day 3 embryo. Indeed, in their hands they demonstrated that this approach actually reduced a woman's chance of having a baby.

    During the intervening decade, advances have been made in many different aspects of the PGS process: blastocyst culture and biopsy, vitrification, and the simultaneous analysis of all twenty-four chromosomes. On its own, each advance has contributed to improved IVF outcomes allowing patients to better plan their families in terms of facilitating single embryo transfer, reducing miscarriage, improving implantation rates and reducing the time to pregnancy (2-6). In combination, they are very powerful and today form the basis of many successful IVF programmes around the world.

    While success stories from an ever-increasing number of IVF centres adopting PGS are compelling, they do not convince everyone. Since 2007, there has been a desire from many clinicians to see more clinical evidence of the benefits of PGS- and rightly so. What is surprising during the past decade is that despite the publication of a growing number of RCTs, observational studies, meta-analysis and national data set analyses investigating the utility of PGS, all of which have shown benefits (3-8), scepticism remains.

    In an era where patient information and informed consent is paramount, it is concerning that most guidelines relating to PGS from professional bodies are out of date and do not reflect the advances made and positive results obtained with PGS (9-11). For this reason, I am excited about the STAR trial (12), which has completed enrolment and the results of which are eagerly anticipated. STAR is a large multicentre, international, blinded RCT which aims to compare the outcomes at 20 weeks following transfer of a single vitrified blastocyst screened using the VeriSeq™ PGS assay versus an unscreened vitrified blastocyst.

    Will this trial, if successful, be enough to move the sceptics? I hope that patients undergoing IVF are given all the information they need to make an informed decision.

    Click here to download and listen to the June 14 webinar from Mr. Stuart Lavery of Hammersmith and Queen Charlotte’s & Chelsea Hospitals, London, on how IVF units are investigating the utility of PGS to ensure the most viable embryo is transferred. Mr. Lavery will share his PGS experience in routine practice and his participation in the STAR study.

    References:

    1. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, Vogel NE, Arts EG, de Vries JW, Bossuyt PM, Buys CH, Heineman MJ, Repping S, van der Veen F.Glujovsky D1, Blake D, Farquhar C, Bardach A. In vitro fertilization with preimplantation genetic screening. N Engl J Med.2007 Jul 5;357(1):9-17.
    2. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev.2012 Jul 11;(7):CD002118.
    3. Forman EJ, Hong KH, Ferry KM, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril.2013;100(1):100-107.e101
    4. Yang Z, Liu J, Collins GS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet.2012;5(1):24.
    5. Scott RT, Upham KM, Forman EF, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases IVF IRs and delivery rates: a randomized controlled trial. Fertil. Steril. 2013; 100(3):697-703.
    6. Forman EJ, Tao X, Ferry KM, Taylor D, Treff NR, Scott Jr R.T. Single embryo transfer with comprehensive chromosome screening results in improved ongoing pregnancy rates and decreased miscarriage rates. Human Reprod. 2012;27(4):1217-22.
    7. Lee E, Illingworth P, Wilton L, Chambers GM. The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod.2015;30(2):473-483.
    8. Chang J, Boulet SL, Jeng G, Flowers L, Kissin DM. (2016) Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States Assisted Reproductive Technology Surveillance Data, 2011-2012. Fertil Steril.105(2):394-400.
    9. Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005291. Review.
    10. Anderson RA, Pickering S. The current status of preimplantation genetic screening: British Fertility Society Policy and Practice Guidelines. Hum Fertil(Camb). 2008 Jun;11(2):71-5.
    11. Harper J, Coonen E, De Rycke M, Fiorentino F, Geraedts J, Goossens V, Harton G, Moutou C, Pehlivan Budak T, Renwick P, Sengupta S, Traeger-Synodinos J, Vesela K. What next for preimplantation genetic screening (PGS)? A position statement from the ESHRE PGD Consortium Steering Committee.Hum Reprod. 2010 Apr;25(4):821-3.
    12. Single Embryo TrAnsfeR of Euploid Embryo (STAR) ClinicalTrials.gov Identifier: NCT02268786

     

     

     

     

     

  4. At Illumina, we recognize that as genetic testing becomes more commonplace and complex, the need for education will continue to grow. Journal publications, scientific conferences, news media sources, and even social media sites share updates and information about popular test options like prenatal screening. Specific testing information regarding non-invasive prenatal testing (NIPT) and marketing materials are available through Illumina’s accredited clinical lab. However, there may be individuals looking for information on prenatal screening that need to start with a basic genetics refresher before moving forward. 

    As part of Illumina's ongoing effort to provide our customers with educational support, the Reproductive and Genetic Health Genetics team developed a series of brief modules entitled, "Noninvasive Prenatal Testing: Background, science, and clinical implementation.” We are pleased to release the first two of these modules: 

    Module 1, entitled “Chromosomes, DNA, and Review of Aneuploidy Syndromes” discusses basic genetic concepts, including meiosis, and reviews causes and features of common aneuploidy syndromes, such as Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18). 

    Module 2, entitled “Overview of Screening Terminology and Available Aneuploidy Testing Options” aims to provide a basic understanding of common screening terms, including sensitivity, specificity, and predictive values. In addition, this module aims to improve awareness of available prenatal screening and testing options.

    These modules are designed to be watched (and re-watched) at one’s own pace.  For those reference laboratories or national laboratory partners looking for more information on NIPT for their employees, to clinicians who need a quick review of available prenatal screening options, to prospective parents interested in learning more about these topics, these modules are for YOU.  Stay tuned for the next installments later this spring!

     

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