Biology subjects

Goldberg, J. D.

Publications and source records attributed to Goldberg, J. D..

4 recordsLinked to original sources

bioRxiv2018

A Data-Driven Evaluation of the Size and Content of Expanded Carrier Screening Panels

PurposeThe American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of non-carriers, one criterion requires a per-condition carrier rate greater than 1-in-100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel-design criteria on at-risk couple detection warrants data-driven evaluation.\n\nMethodsCarrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and evaluated for panels satisfying various criteria. Condition-specific clinical detection rate was estimated via simulation.\n\nResultsDifferent interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11%-81% fewer at-risk couples, and detect 36%-79% fewer carriers than a 176-condition panel. If the carrier-rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that clinical detection rate remains >84% for conditions with carrier rates as low as 1-in-1000.\n\nConclusionsThe 1-in-100 criterion limits at-risk couple detection and should be reconsidered.

genetics↗

bioRxiv2016

Noninvasive Prenatal Screening at Low Fetal Fraction: Comparing Whole- Genome Sequencing and Single-Nucleotide Polymorphism Methods

ObjectivePerformance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies.\n\nMethodsComputational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations.\n\nResultsThe SNP methods performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples.\n\nConclusionThe WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures.

genomics↗

bioRxiv2016

Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates

Objective: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences.\n\nDesign: Retrospective analysis of patients from the general population who have undergone carrier screening for SLOS.\n\nSetting: Individuals were offered and elected carrier screening in their respective physicians offices.\n\nPatients: 262,399 individuals with no indication of family or personal history of Smith-Lemli-Opitz syndrome, primarily US-based, screened for Smith-Lemli-Opitz syndrome mutations as part of an expanded carrier screening panel.\n\nIntervention(s): Data on mutations in the DHCR7 gene causing SLOS were analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature are then compared to our data to estimate the effect of SLOS on fetal survival.\n\nMain Outcome Measure(s): Individual and cumulative allele frequencies stratified by self-reported patient ethnicity.\n\nResults: SLOS carrier frequency is highest in individuals of Ashkenazi Jewish ancestry (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence to that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience fetal demise.\n\nConclusion: SLOS is relatively frequent in certain populations and, due to its impact on fetal survival, merits preconception screening.

genetics↗

bioRxiv2016

Systematic Design and Comparison of Expanded Carrier Screening Panels

Purpose: The recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.\n\nMethods: Guided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.\n\nResults: Based on modeled fetal risks for \"severe\" and \"profound\" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screens sensitivity is greatly impacted by two factors: (1) the methodology used (e.g., full-exon sequencing finds up to 46 more affected fetuses per 100,000 than targeted genotyping with an optimal 50 variant panel), and (2) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome, spinal muscular atrophy, 21-hydroxylase deficiency, and alpha-thalassemia account for 54 affected fetuses per 100,000).\n\nConclusion: The described approaches allow principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

genetics↗