Performance of single-gene noninvasive prenatal testing for autosomal recessive conditions in a general population setting.

OBJECTIVE: Carrier screening with reflex to single-gene noninvasive prenatal testing (sgNIPT) is an alternative approach for identifying pregnancies at risk for inherited autosomal recessive conditions without the need for a sample from the reproductive partner. This study is the largest clinical validation of this approach in a general population setting. METHODS: The clinical performance of carrier screening with reflex to sgNIPT for cystic fibrosis, spinal muscular atrophy, alpha thalassemias, and beta hemoglobinopathies was assessed by collecting pregnancy outcome data on patients who underwent this testing and comparing the neonatal outcome to the assay-predicted fetal risk. RESULTS: Of 42,067 pregnant individuals who underwent screening, 7538 carriers (17.9%) had reflex sgNIPT, and neonatal or fetal outcomes were obtained for 528 cases, including 25 affected pregnancies. Outcomes demonstrated high concordance with sgNIPT, for example, all pregnancies with 9 in 10 personalized fetal risk results were affected (positive predictive value (PPV) of 100% for the sub-group) and the sgNIPT assay showed a sensitivity of 96.0% (95% CI: 79.65%-99.90%), specificity of 95.2% (95% CI: 92.98%-96.92%), average PPV of 50.0% (95% CI: 35.23%-64.77%), and negative predictive value (NPV) of 99.8% (95% CI: 98.84%-99.99%). The end-to-end performance of carrier screening with reflex to sgNIPT was calculated to have a sensitivity of 92.4% and specificity of 99.9%, which are unaffected by partner carrier screening or misattributed paternity unlike a traditional carrier screening workflow, which has a 35% sensitivity and a maximum of 25% PPV (1 in 4) in a real-life setting. CONCLUSION: This study builds upon earlier findings to confirm that carrier testing with reflex to sgNIPT is highly accurate for general population screening. Given this high accuracy and an NPV of 99.8%, this workflow should be considered as an option for most of the general pregnant population. When the biological partner sample is unavailable, this workflow should be recommended as the first-line approach.

Validation of a non-invasive prenatal test for fetal RhD, C, c, E, K and Fya antigens.

We developed and validated a next generation sequencing-(NGS) based NIPT assay using quantitative counting template (QCT) technology to detect RhD, C, c, E, K (Kell), and Fya (Duffy) fetal antigen genotypes from maternal blood samples in the ethnically diverse U.S. population. Quantitative counting template (QCT) technology is utilized to enable quantification and detection of paternally derived fetal antigen alleles in cell-free DNA with high sensitivity and specificity. In an analytical validation, fetal antigen status was determined for 1061 preclinical samples with a sensitivity of 100% (95% CI 99-100%) and specificity of 100% (95% CI 99-100%). Independent analysis of two duplicate plasma samples was conducted for 1683 clinical samples, demonstrating precision of 99.9%. Importantly, in clinical practice the no-results rate was 0% for 711 RhD-negative non-alloimmunized pregnant people and 0.1% for 769 alloimmunized pregnancies. In a clinical validation, NIPT results were 100% concordant with corresponding neonatal antigen genotype/serology for 23 RhD-negative pregnant individuals and 93 antigen evaluations in 30 alloimmunized pregnancies. Overall, this NGS-based fetal antigen NIPT assay had high performance that was comparable to invasive diagnostic assays in a validation study of a diverse U.S. population as early as 10 weeks of gestation, without the need for a sample from the biological partner. These results suggest that NGS-based fetal antigen NIPT may identify more fetuses at risk for hemolytic disease than current clinical practice, which relies on paternal genotyping and invasive diagnostics and therefore is limited by adherence rates and incorrect results due to non-paternity. Clinical adoption of NIPT for the detection of fetal antigens for both alloimmunized and RhD-negative non-alloimmunized pregnant individuals may streamline care and reduce unnecessary treatment, monitoring, and patient anxiety.

Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions.

PURPOSE: The purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening. METHODS: An unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies. RESULTS: Overall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected. CONCLUSION: Although traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (∼10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.

Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost.

OBJECTIVE: To evaluate the clinical benefits and achievable cost savings associated with the adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care. METHOD: A decision-analytic model was developed to compare carrier screen with reflex sgNIPT (maternal carrier status and fetal risk reported together) as first-line carrier screening to the traditional carrier screening workflow (positive maternal carrier screen followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and healthcare costs associated with the two screening methods. These results were used to simulate appropriate pricing for reflex sgNIPT. RESULTS: Reflex sgNIPT carrier screening-detected 108 of 110 affected pregnancies per 100,000 births (98.5% sensitivity), whereas traditional carrier screening-detected 46 of 110 affected pregnancies (41.5% sensitivity). The cost to identify one affected pregnancy was reduced by 62% in the reflex sgNIPT scenario compared to the traditional scenario. Adding together the testing cost savings and the savings from earlier clinical intervention made possible by reflex sgNIPT, the total cost savings was $37.6 million per 100,000 pregnancies. Based on these cost savings, we simulated appropriate reflex sgNIPT pricing range: if the cost to identify one affected pregnancy is the unit cost, carrier screening with reflex sgNIPT can be priced up to $1,859 per test (or $7,233 if sgNIPT is billed separately); if the cost per 100,000 pregnancies is the unit cost, carrier screening with sgNIPT can be priced up to $1,070 per test (or $2,336 if sgNIPT is billed separately). CONCLUSION: Using the carrier screen with reflex sgNIPT as first-line screening improves the detection of affected fetuses by 2.4-fold and can save costs for the healthcare system. A real-life experience will be needed to assess the clinical utility and exact cost savings of carrier screen with reflex sgNIPT.

40 years and beyond for the National Society of Genetic Counselors: Reflections on genetic counseling practice.

The National Society of Genetic Counselors (NSGC) was established in 1979 and has grown from a small dedicated group of genetic counselors to over 5,000 certified genetic counselors in 2019. During this time period, there have been tremendous advances in the practice of genetic counseling, the availability of genetic testing, and the use of technology. These advances have significantly changed our roles and responsibilities and have contributed to the expansion and diversification of our field in clinical and non-clinical work settings. The launch of genetic counseling services in prenatal, pediatric, and adult genetics clinics has expanded to many medical specialties. Genetic counselors are also working in industry, public health, policy, education, research, and other work settings. With growth into new areas and the significant increase in the number of practitioners, genetic counselors have established themselves professionally and created opportunities where they can not only contribute to the delivery of quality genetic services, but lead the way. The counseling skills that are a core part of training as genetic counselors will continue to have broad application in diverse work settings and roles. Looking to the future, genetic counselors need to proactively consider tasks that artificial intelligence and other technologies can accomplish so that genetic counselors have the bandwidth to use their expertise to successfully and efficiently meet the growing demands for genetic counseling services. During the 40th anniversary celebration at the 2019 NSGC Annual Conference, three of NSGC's past presidents reflected on the early years of NSGC and clinical practice, recognized key accomplishments and where the profession stands today, and shared thoughts about the future of genetic counseling. Videos of the actual talks can be accessed by internet search 'NSGC Celebrates 40 Years' (https://www.nsgc.org/p/bl/et/blogid=53&blogaid=1162). A timeline of the genetic counseling profession is available at https://www.nsgc.org/page/nsgc-timeline.

Exploring experiences and expectations of prenatal health care and genetic counseling/testing in immigrant Latinas.

As the Latino population of the United States continues to increase, the specific needs of Latinos in genetic counseling continue to be unmet. Using culturally tailored genetic counseling responsive to the needs of the patient can assist in building rapport in genetic counseling sessions. We aimed to investigate the relationship between acculturation, prenatal care, genetic testing experiences, and expectations for prenatal care in an immigrant Latino population. A total of 20 Spanish-speaking, pregnant Latinas from various Latin American countries were interviewed after completing a prenatal genetic counseling session. The semi-structured phone interview included questions about the participants' experiences with genetic counseling/testing, prenatal health care in their home country, their current prenatal care in the United States, and information they felt to be important to know during their pregnancy. Although this study showed no statistically significant associations between acculturation, prenatal care, and genetic counseling/testing experiences, six significant content domains were identified as relevant to the participants. Overall, we found that immigrant Latinas desire to know prenatal risk information to help them prepare, relieve guilt, and help make screening/testing/family planning decisions. These Latinas reported the genetic counselor provided confidence, a sense of autonomy, and empowerment, for them to make their own decisions regarding prenatal screening/testing. The participants also spoke about stressors unique to the immigrant population, most notably being away from their older children and other family members. Identifying relevant factors about the lived experience of this population can help genetic counselors better address possible needs, feelings of guilt, and/or isolation and identifying women who could benefit from group-based prenatal care, support groups, or referrals to social work.

Genetic counseling job market in the United States and Canada: An analysis of job advertisements 2014-2016.

Genetic counseling careers continue to evolve, yet there remains a lack of information about hiring trends in the genetic counseling profession. In this study, job advertisements in the United States and Canada were analyzed, using the National Society of Genetic Counselors (NSGC) Job Connections and the American Board of Genetic Counseling (ABGC) eBlasts from 2014 to 2016 to appraise job roles, qualifications, settings, specialties, and type. NSGC had 1875 advertised openings from 2014 to 2016, while ABGC had 373 advertised openings. Jobs containing a "counseling" role increased as a percentage from 2014 to 2016 when advertised by NSGC (χ2  = 25.52, p < 0.000001) but decreased each year from 2014 to 2016 as a percentage when advertised through ABGC (χ2  = 14.29, p = 0.0008). In the ABGC job postings, it was noted that 36% of job postings were advertised for other specialties (not solely cancer, pediatric, or prenatal) in 2014, and increased to 67% in 2016 (χ2  = 10.09, p = 0.02). Examining the job specialties posted by ABGC and NSGC, several new or unique roles were found in the job advertisements such as ophthalmology counselor, variant curator, rare diseases information specialist, and clinical policy analyst. Roles for temporary, contract or fellowship positions are possibly becoming more common, along with small upturns in positions that are off-site or remote. In analyzing the changing workforce, there was a statistically significant decrease identified in jobs advertised by NSGC in the laboratory setting from 28% in 2014 to 17% in 2016 (χ2  = 24.12, p = 0.000024). This information on the evolving career of genetic counseling is valuable for the current workforce and training programs as they adapt with the changing landscape of the profession.

Clinical experience with sex chromosome aneuploidies detected by noninvasive prenatal testing (NIPT): Accuracy and patient decision-making.

OBJECTIVE: The objectives of the study are to assess the accuracy of noninvasive prenatal testing (NIPT) for sex chromosome aneuploidies (SCAs) and to investigate patient decision-making in clinical practice. STUDY DESIGN: This is a retrospective cohort study review of positive NIPT results for SCAs from January 2013 to September 2017. RESULTS: Of the 136 positive NIPT results for SCAs, 73 (53.7%) were positive for 45,X, 62 (45.6%) were a sex chromosome trisomy, and 1 was a sex chromosome tetrasomy. Of the 134 viable pregnancies, 46 (34.3%) elected to pursue prenatal diagnosis. Fewer women underwent invasive prenatal testing when counseled regarding a positive NIPT for monosomy X in the presence of suggestive ultrasound findings (4/23; 17.4%) compared with those who had a positive NIPT result without ultrasound findings (24/46, 52.2%). Abnormal karyotypes consistent with the NIPT result were confirmed in 30/64 (46.9%). Even in the context of ultrasound abnormalities, there was not 100% concordance. CONCLUSIONS: The majority (88/134; 65.7%) of patients in our cohort declined prenatal diagnosis even in the presence of associated ultrasound findings. Comprehensive pretest and posttest counseling is recommended and should address the importance of confirmatory testing and benefits of early diagnosis. Practice guidelines are needed to address provider responsibilities about postnatal testing.

Genetic Counseling Overview for the Obstetrician-Gynecologist.

This article outlines a framework for the process of genetic counseling in the primary obstetric and gynecologic setting. Specifics regarding risk assessment, family history evaluation, genetic testing, and pretest and posttest counseling are discussed. Additionally, the article provides strategies for counseling patients effectively and addresses when a referral for additional genetic counseling by a specialized genetics provider should be considered.

Genesurance Counseling: Patient Perspectives.

Genetic counselors (GCs) have reported an increase in discussion of insurance-related, or "genesurance," topics during genetic counseling sessions. Despite increasing frequency, there have been no studies examining patient expectations of GCs in these discussions. This study aimed to explore patient expectations of GCs in these discussions, as well as examine factors that may impact expectations. A 38-item survey was administered prior to patients receiving prenatal or cancer genetic counseling at 11 clinic sites across UTHealth, Baylor College of Medicine, and Sanford Health, with 360 responses analyzed. Key variables were analyzed using descriptive statistics, chi-square analysis, and multivariate logistic regression to assess associations between factors and control for potential confounders. Over 75% of patients expected GCs to discuss genesurance topics during a genetic counseling session. The majority of patients (78%) expected GCs to provide an estimated out-of-pocket cost, know if a test is a covered benefit (77%), and provide referral information for further questions (76%). Two additional expectations, considered to be unrealistic in most clinical settings, included expecting GCs to know the patient's specific insurance plan and coverage information (57%) and provide an exact out-of-pocket cost (41%). Ethnicity was the only significant predictor of response for these two expectations, as African Americans and Hispanics were more likely than Caucasians to have these beliefs. While the patient participants felt that GCs were primarily responsible for initiating these conversations, they also reported a personal sense of responsibility for raising questions. This study demonstrates that patients may expect GCs to address genesurance topics in a genetic counseling session, with specific expectations about the cost and coverage of genetic tests. Further studies will establish the most effective way to communicate this information to patients and examine whether and where within the scope of GC practice, genesurance discussions fall.

Projecting the Supply and Demand for Certified Genetic Counselors: a Workforce Study.

As of May 2017, there were 4242 Certified Genetic Counselors (CGC) (American Board of Genetic Counseling, Inc. 2017) and 41 graduate-level genetic counseling training programs (Accreditation Council for Genetic Counseling 2017) in North America, and the demand for CGCs continues to increase. In the Fall of 2015 the Genetic Counselor Workforce Working Group, comprised of representatives from the American Board of Genetic Counseling (ABGC), the Accreditation Council for Genetic Counseling (ACGC), the Association of Genetic Counseling Program Directors (AGCPD), the American Society of Human Genetics (ASHG), and the National Society of Genetic Counselors (NSGC) commissioned a formal workforce study to project supply of and demand for CGCs through 2026. The data indicate a shortage of genetic counselors engaged in direct patient care. Assuming two scenarios for demand, supply is expected to reach equilibrium between 2024 and 2030. However, given the rate of growth in genetic counseling training programs in the six months since the study was completed, it is reasonable to expect that the number of new programs may be higher than anticipated by 2026. If true, and assuming that growth in programs is matched by equivalent growth in clinical training slots, the supply of CGCs in direct patient care would meet demand earlier than these models predict.

Physicians' Awareness and Utilization of Genetic Services in Texas.

The number of disorders for which genetic testing is available has increased nearly 500% in the past 15 years. Access to genetic tests and services often hinges on physicians' ability to identify patients at risk for genetic disease and provide appropriate testing and counseling or refer to genetic specialists. Recent research demonstrates the need for referrals to genetic specialists by showing that many physicians lack skills required to perform appropriate genetic services, such as making proper risk assessments, providing genetic counseling, ordering genetic testing and interpreting results. However, little research exists on physicians' awareness and utilization of genetic services. In this study, an electronic survey evaluating practicing physicians' awareness of, utilization of and perceived barriers to genetic services in Texas, and interest in learning more about genetics and genetic services was distributed via state physician organizations. Of the 157 participants, approximately half reported they were moderately or very aware of genetic testing and services in their area. Very few reported awareness of telemedicine services. Over two-thirds reported never or rarely referring to genetic counselors or other genetic specialists, despite 75% reporting they had noticed an increased impact of genetics on their field and 61% reporting they had discussed genetics more in their day-to-day practice in the last 5-10 years. Only 20% reported genetics was very integral to their specialty. Over three-fourths of all participants indicated interest in learning more about genetics, genetic testing, and genetic services. Among the most frequently chosen barriers to genetic counselors were awareness-related barriers such as not knowing how to refer to a genetic counselor. Responses to many items varied significantly by medical specialty. The results identify a need to increase awareness of genetic services and referral logistics. Specific findings can help direct outreach efforts to educate clinicians, such as developing clinically meaningful, specialty-specific educational objectives.

Relieving the Bottleneck: An Investigation of Barriers to Expansion of Supervision Networks at Genetic Counseling Training Programs.

Rapid growth in the demand for genetic counselors has led to a workforce shortage. There is a prevailing assumption that the number of training slots for genetic counseling students is linked to the availability of clinical supervisors. This study aimed to determine and compare barriers to expansion of supervision networks at genetic counseling training programs as perceived by supervisors, non-supervisors, and Program Directors. Genetic counselors were recruited via National Society of Genetic Counselors e-blast; Program Directors received personal emails. Online surveys were completed by 216 supervisors, 98 non-supervisors, and 23 Program Directors. Respondents rated impact of 35 barriers; comparisons were made using Kruskal-Wallis and Wilcoxon ranked sum tests. Half of supervisors (51%) indicated willingness to increase supervision. All non-supervisors were willing to supervise. However, all agreed that being too busy impacted ability to supervise, highlighted by supervisors' most impactful barriers: lack of time, other responsibilities, intensive nature of supervision, desire for breaks, and unfilled positions. Non-supervisors noted unique barriers: distance, institutional barriers, and non-clinical roles. Program Directors' perceptions were congruent with those of genetic counselors with three exceptions they rated as impactful: lack of money, prefer not to supervise, and never been asked. In order to expand supervision networks and provide comprehensive student experiences, the profession must examine service delivery models to increase workplace efficiency, reconsider the supervision paradigm, and redefine what constitutes a countable case or place value on non-direct patient care experiences.

Finding Middle Ground in Constructing a Clinically Useful Expanded Carrier Screening Panel.

Expanded carrier screening for autosomal-recessive conditions effectively identifies more carrier couples than traditional guideline-based carrier screening. However, clinically available expanded carrier screening panels include numerous conditions, some of which have questionable clinical utility as a result of very low carrier frequency, low or unknown testing sensitivity, and mild or incompletely penetrant phenotypes. Using the 2013 American College of Medical Genetics and Genomics Position Statement on Prenatal and Preconception Expanded Carrier Screening and the 2017 American College of Obstetricians and Gynecologists' Committee Opinion on Carrier Screening in the Age of Genomic Medicine as guidance, we propose specific criteria for the development of expanded carrier screening panels that will maximize clinical utility and minimize patient stress, unnecessary cost of follow-up testing, and clinician time spent facilitating and performing follow-up counseling and testing. We identified 96 conditions that meet our proposed criteria, far more than current guidelines recommend. On the other hand, a considerable percentage (73%) of conditions on current expanded carrier screen panels does not meet our proposed criteria. The purpose of this commentary is to acknowledge the benefits of expanded panels, but to also recognize that in their current state, we are putting patients at risk for undue stress and spending excessive time and money on follow-up testing for remarkably rare or mild conditions and conditions with low screening performance. We encourage laboratories and clinicians to work together to create the most clinically useful screening panels for patients desiring reproductive risk information.