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Maternal-fetal medicine owes much of its successes in recent decades to the contributions of the clinical laboratory. Yet recent controversy around noninvasive prenatal screening (NIPS) shows that laboratorians have work to do in order to ensure clinicians can translate advances in medical technology into better patient care.

In particular, when it comes to prenatal screening for rare conditions, the stakes are high, and the statistics can be confusing. The January 2022 New York Times article “When They Warn of Rare Disorders, These Prenatal Tests Are Usually Wrong,” has drawn attention to potentially misleading results of positive prenatal genetic screens for rare microdeletions. The authors highlight how the screening tests’ low positive predictive value contrasts with the information on some manufacturers’ brochures that claim their assays are “reliable” and “highly accurate,” offering “total confidence” for pregnant patients.

Six of the test manufacturers interviewed by the Times stated that patients with a positive screen should always review results with their healthcare provider and “cautioned that the tests are meant not to diagnose a condition but rather to identify high-risk patients in need of additional testing.” However, with these tests often performed outside the healthcare provider’s purview—and with limited time for interactions with their patients—the potential for misunderstandings abounds.

The lab community can help clarify these results by working with clinicians to improve understanding about what the prenatal screens are, the potential issues around screening results, and the most appropriate language to help clearly communicate results to healthcare providers and patients, experts told CLN.

NIPS: Aneuploidy vs. Microdeletion

Prenatal genetic screening has been available for decades. One of the earliest and most common NIPS tests is for trisomy 21 (Down syndrome). For women at higher risk for this chromosomal aneuploidy (having a third copy of chromosome 21), a definitive answer can be obtained via a diagnostic test. Historically, fetal cells would be obtained via amniocentesis and then karyotyped.

With the discovery of fetal cell-free DNA (cfDNA) in maternal blood, advances in DNA sequencing technology, and extensive bioinformatics, individual laboratories began offering NIPS for far less common genetic conditions called microdeletions—missing or extra pieces of chromosomes. Among these are Prader-Willi syndrome (1 in 20,000 births), Cri-du-chat syndrome (1 in 15,000 births), and DiGeorge syndrome (1 in 4,000 births).

NIPS for these rare syndromes is at the heart of the Times article because most positive screens for microdeletions would not be confirmed by positive diagnostic tests. In fact, they can be overwhelmingly incongruous, with some screens averaging only 15 diagnostically confirmed correct calls out of 100 screen-positive test results. Here is where things can get tricky for many clinicians and patients: Technically, these NIPS are not diagnostic tests, and they are not “wrong.”

If the results can be so confusing, why are these prenatal screens for very rare genetic conditions so popular? “A driving force for the growth of NIPS is the significant interest from patients and clinicians,” said Jonathan Genzen, MD, PhD, chief operations officer, ARUP Laboratories, and associate professor, University of Utah Department of Pathology, Salt Lake City. Another driving force is the commercial nature of these tests and manufacturers’ broad marketing efforts.

It is recommended that all pregnant individuals be offered information about prenatal screening and diagnostic testing—what assays are available and what information they can and cannot provide about a developing fetus. However, many professional societies, including the American College of Medical Genetics and Genomics and the American College of Obstetricians and Gynecologists, advise against prenatal screening for microdeletions.

From a laboratorian perspective, the problem with NIPS could be a matter of language: To accurately report a NIPS result, one must use statistical terminology that is not common knowledge and hope that it is correctly communicated to patients by their physicians or genetic specialists.

NIPS Statistics 101

The language used to describe NIPS performance is important and very specific. Manufacturers must release information about a screening test’s detection rate, false-positive rate, and estimated positive predictive value:

Detection rate. The detection rate (DR) refers to the proportion of all individuals with a specific condition that is correctly identified as being positive by a test. For example, if 100 tested individuals have a given condition and 99 test positive, the test’s DR is 99%. Another name for DR is sensitivity.

False-positive rate. The false-positive rate (FPR) indicates the proportion of all individuals without that specific condition that an assay incorrectly identifies as being positive. For example, if 10,000 tested individuals do not have the given condition and 100 test positive, the test’s FPR is 1%.

Positive predictive value. The positive predictive value (PPV) combines DR and FPR with the prevalence of the specific condition. PPV represents the proportion of individuals with a positive test who have the specific condition. For example, a PPV of 50% means half of those with a positive test truly have the specific condition. Even though the DR and FPR remain constant, the PPV of a test will vary based on the prevalence of the condition in a defined population. In general, the rarer the condition, the lower the PPV.

The authors of the Times article focused only on the PPV of NIPS for microdeletions. Prader-Willi syndrome (PWS) has a very low prevalence of about 1:20,000 and NIPS provided a relatively low PPV of 15%. “With such a low prevalence,” said Glenn Palomaki, PhD, professor in the department of pathology and laboratory medicine, Women & Infants Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, “even an excellent test could have a low PPV.”

These statistics can seem contradictory and could be the reason why some manufacturers highlight DR and FPR in their informational brochures. If the prevalence of PWS were much higher at 1:400 (the prevalence of Down syndrome), the PPV of that same test would increase to over 90%.

Statistical concepts like DR, FPR, and PPV are taught to clinical professionals but are not well understood by the general public. Therefore, it is imperative to communicate the purpose and limitations of NIPS—particularly for uncommon disorders such as microdeletions.

Communicating Screening Results

Screening results for microdeletions, especially positive screens that are not diagnostically confirmed, have confused and stressed patients, prompting potentially difficult discussions and decisions—all within a finite gestational timeline.

“The NYT article authors got a lot of criticism for their use of the word ‘wrong’ when referring to microdeletion screening results,” said Katie Stoll, MS, LGC, executive director of the Genetic Support Foundation, based in Olympia, Washington. “The way the test reports are often phrased makes it seem like the presence of the condition is certain, and so if a patient gets a positive screen and a subsequent negative diagnostic test, the patient often does feel the screening results are wrong.”

Stoll, who still counsels patients, added: “We’re talking with people about their pregnancies. Misunderstandings can result in tragic or misguided decisions—a lot of anguish. These issues have been here since cfDNA testing began about a decade ago. The Times article drew attention to it—attention that I think is overdue.”

“Sometimes the healthcare providers don’t have the time or resources to really explain what a screening test means to their patients,” Palomaki said. His advice to laboratorians? “In your reports to clinicians, make sure you use language like ‘screen positive.’ Very few physicians will see ‘screen positive’ and translate that to, ‘Your baby has this genetic issue.’”

It is also worth noting that patients often see laboratory results through their electronic health records before they talk with their provider. “In the future,” Palomaki added, “this is something labs may need to address to ensure screening results are very readable and clear for the lay public.”

“Clinicians should have resources to better understand and communicate screening test results to patients, and laboratories performing such testing should make sure that informational resources and test reports provide thorough, understandable, and patient-centric explanations,” Genzen added. “The Food and Drug Administration may describe this in the context of ‘labeling’ of tests. I’d suggest it’s also just good patient care and medical practice.”

While prenatal screens for microdeletions offer new opportunities for increasing patient knowledge about their pregnancies, positive screening results are not indicative of a genetic syndrome. Clinical laboratorians should take caution and care when communicating screening information to clinicians and patients.

Sarah Michaud is a freelance writer who lives in London. +Email: [email protected]

Sources for Reliable, Independent NIPS Guidance

American College of Obstetrics and Gynecology (ACOG)

ACOG produces practice guidelines for healthcare professionals and educational materials for patients, provides practice management and career support, facilitates programs and initiatives to improve women’s health, and advocates for members and patients.

Genetic Support Foundation (GSF)

GSF is a not-for-profit organization whose mission is to improve the quality of healthcare by providing up-to-date, objective genetic information to patients, providers, and healthcare organizations, supporting those in need of genetic services, and facilitating the adoption of best genetic practices.

Society for Maternal and Fetal Medicine (SMFM)

SMFM is a nonprofit organization that supports the clinical practice of maternal-fetal medicine by providing education, promoting research, and engaging in advocacy to optimize the health of high risk pregnant women and their babies.