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

ABSTRACTPurposeThe 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.MethodsCarrier 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.ResultsDifferent 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.ConclusionsThe 1-in-100 criterion limits at-risk couple detection and should be reconsidered.

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Clinical Implementation of Expanded Carrier Screening in Pregnant Women at Early Gestational Weeks: A Chinese Cohort Study

Genes ◽

10.3390/genes12040496 ◽

2021 ◽

Vol 12 (4) ◽

pp. 496

Author(s):

Mengmeng Shi ◽

Angeline Linna Liauw ◽

Steve Tong ◽

Yu Zheng ◽

Tak Yeung Leung ◽

...

Keyword(s):

At Risk ◽

Pregnant Women ◽

Carrier Screening ◽

Sequential Testing ◽

Carrier Status ◽

Carrier Rate ◽

Male Partners ◽

Clinical Implementation ◽

Clinical Value ◽

Expanded Carrier Screening

Demands for expanded carrier screening (ECS) are growing and ECS is becoming an important part of obstetrics practice and reproductive planning. The aim of this study is to evaluate the feasibility of a small-size ECS panel in clinical implementation and investigate Chinese couples’ attitudes towards ECS. An ECS panel containing 11 recessive conditions was offered to Chinese pregnant women below 16 gestational weeks. Sequential testing of their partners was recommended for women with a positive carrier status. The reproductive decision and pregnancy outcome were surveyed for at-risk couples. A total of 1321 women performed ECS successfully and the overall carrier rate was 19.23%. The estimated at-risk couple rate was 0.83%. Sequential testing was performed in less than half of male partners. Eight at-risk couples were identified and four of them performed prenatal diagnosis. Our study demonstrated that a small-size ECS panel could yield comparable clinical value to a larger-size panel when the carrier rate of the individual condition is equal or greater than 1%. In addition, more than half of male partners whose wives were carriers declined any types of sequential testing possibly due to a lack of awareness and knowledge of genetic disorders. Genetic education is warranted for the better implementation of ECS.

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Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At-Risk Couples

10.1101/069393 ◽

2016 ◽

Cited By ~ 3

Author(s):

Caroline Ghiossi ◽

James D. Goldberg ◽

Imran S. Haque ◽

Gabriel A. Lazarin ◽

Kenny K. Wong

Keyword(s):

Decision Making ◽

At Risk ◽

Clinical Utility ◽

Carrier Screening ◽

Reproductive Behaviors ◽

Reproductive Risk ◽

Expanded Carrier Screening ◽

Reproductive Decision Making ◽

Recessive Genes ◽

Professional Guidelines

ABSTRACTPurposeExpanded carrier screening (ECS) analyzes dozens or hundreds of recessive genes for determining reproductive risk. Data on clinical utility of screening conditions beyond professional guidelines is scarce.MethodsIndividuals underwent ECS for up to 110 genes. 537 at-risk couples (ARC), those in which both partners carry the same recessive disease, were invited to a retrospective IRB-approved survey of their reproductive decision making after receiving ECS results.Results64 eligible ARC completed the survey. Of 45 respondents screened preconceptionally, 62% (n=28) planned IVF with PGD or prenatal diagnosis (PNDx) in future pregnancies. 29% (n=13) were not planning to alter reproductive decisions. The remaining 9% (n=4) of responses were unclear.Of 19 pregnant respondents, 42% (n=8) elected PNDx, 11% (n=2) planned amniocentesis but miscarried, and 47% (n=9) considered the condition insufficiently severe to warrant invasive testing. Of the 8 pregnancies that underwent PNDx, 5 were unaffected and 3 were affected. 2 of 3 affected pregnancies were terminated.Disease severity was found to have significant association (p=0.000145) with changes in decision making, whereas guideline status of diseases, controlled for severity, was not (p=0.284).ConclusionMost ARC altered reproductive planning, demonstrating the clinical utility of ECS. Severity of conditions factored into decision making.

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A data driven approach for determining the optimal content for expanded carrier screening panels

Fertility and Sterility ◽

10.1016/j.fertnstert.2018.07.438 ◽

2018 ◽

Vol 110 (4) ◽

pp. e148

Author(s):

R. Ben-Shachar ◽

A. Svenson ◽

D. Muzzey

Keyword(s):

Carrier Screening ◽

Data Driven ◽

Expanded Carrier Screening ◽

Data Driven Approach

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Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels

10.1101/429050 ◽

2018 ◽

Author(s):

Michael H. Guo ◽

Anthony R. Gregg

Keyword(s):

At Risk ◽

Exome Sequencing ◽

East Asian ◽

Carrier Screening ◽

Carrier Rate ◽

Ashkenazi Jewish ◽

Careful Selection ◽

Recessive Condition ◽

Selection Of ◽

Genetic Carrier Screening

AbstractPurposePrenatal genetic carrier screening can identify parents at risk of having a child affected by a recessive condition. However, the conditions/genes most appropriate for screening remain a matter of debate. Estimates of carrier rates across genes are needed to guide construction of carrier screening panels.MethodsWe leveraged an exome sequencing database (n=123,136) to estimate carrier rates across 6 major ancestries for 416 genes associated with severe recessive conditions.Results36.5% (East Asian) to 65% (Ashkenazi Jewish) of individuals are variant carriers in at least one of the 416 genes. For couples, screening all 416 genes would identify 0.4-2.8% of couples as being at-risk for having a child affected by one of these conditions. Screening just the 47 genes with carrier rate > 1.0% would identify more than 85% of these at-risk couples. An ancestry-specific panel designed to capture genes with carrier rates > 1.0% would include 6 to 30 genes, while a comparable pan-ethnic panel would include 47 genes.ConclusionOur work guides the design of carrier screening panels and provides data to assist in counseling prospective parents. Our results highlight a high cumulative carrier rate across genes, underscoring the need for careful selection of genes for screening.

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Systematic Design and Comparison of Expanded Carrier Screening Panels

10.1101/080713 ◽

2016 ◽

Cited By ~ 1

Author(s):

Kyle A. Beauchamp ◽

Dale Muzzey ◽

Kenny K. Wong ◽

Gregory J. Hogan ◽

Kambiz Karimi ◽

...

Keyword(s):

Fragile X ◽

Carrier Screening ◽

Medical Society ◽

Systematic Design ◽

Systematic Classification ◽

Expanded Carrier Screening ◽

Mendelian Disorders ◽

High Prevalence ◽

Two Factors ◽

Clinical Detection

AbstractPurposeThe 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.MethodsGuided 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.ResultsBased 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 screen’s sensitivity is greatly impacted by two factors: (1) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping), and (2) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches allow principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

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Clinical Utility of Expanded Carrier Screening: Results-Guided Actionability and Outcomes

10.20944/preprints201808.0020.v1 ◽

2018 ◽

Cited By ~ 2

Author(s):

Katherine Johansen Taber ◽

Kyle A. Beauchamp ◽

Gabriel Lazarin ◽

Dale Muzzey ◽

Aishwarya Arjunan ◽

...

Keyword(s):

Clinical Utility ◽

Diagnostic Testing ◽

Carrier Screening ◽

Limited Data ◽

Affected Offspring ◽

Expanded Carrier Screening ◽

Prenatal Diagnostic ◽

Reproductive Decision Making ◽

The Impact ◽

Prenatal Diagnostic Testing

Purpose: Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. Methods: Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. Results: Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. Conclusions: ECS results impacted couples’ reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.

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