COSMOS: a platform for real-time morphology-based, label-free cell sorting using deep learning.

Cells are the singular building blocks of life, and a comprehensive understanding of morphology, among other properties, is crucial to the assessment of underlying heterogeneity. We developed Computational Sorting and Mapping of Single Cells (COSMOS), a platform based on Artificial Intelligence (AI) and microfluidics to characterize and sort single cells based on real-time deep learning interpretation of high-resolution brightfield images. Supervised deep learning models were applied to characterize and sort cell lines and dissociated primary tissue based on high-dimensional embedding vectors of morphology without the need for biomarker labels and stains/dyes.

Isolation of single circulating trophoblasts from maternal circulation for noninvasive fetal copy number variant profiling.

Objective: To develop a multi-step workflow for the isolation of circulating extravillous trophoblasts (cEVTs) by describing the key steps enabling a semi-automated process, including a proprietary algorithm for fetal cell origin genetic confirmation and copy number variant (CNV) detection.

Methods: Determination of the limit of detection (LoD) for submicroscopic CNV was performed by serial experiments with genomic DNA and single cells from Coriell cell line biobank with known imbalances of different sizes. A pregnancy population of 372 women was prospectively enrolled and blindly analyzed to evaluate the current workflow.

Survey of US obstetrician opinions regarding NIPT use in general practice: implementation and barriers.

Objective: To evaluate the knowledge and opinions of US obstetric providers who use noninvasive prenatal testing (NIPT) to understand current utilization and guide future best practices.

Methods: A questionnaire was designed to assess the level of knowledge and attitudes of OBGYNs toward screening options for aneuploidy, with a focus on NIPT. Initial questions evaluated obstetrician demographics, practice type, and NIPT familiarity.

Clinical performance of non-invasive prenatal testing (NIPT) using targeted cell-free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies.

Objective: To evaluate the clinical performance of non-invasive prenatal testing for trisomy 21, 18, and 13 using targeted cell-free DNA (cfDNA) analysis.

Methods: Targeted cfDNA analysis using DANSR™ and FORTE™ with microarray quantitation was used to evaluate the risk of trisomy 21, 18, and 13 in blinded samples from 799 singleton, twin, natural, and IVF pregnancies. Subjects either had fetal chromosome evaluation by karyotype, FISH, QF-PCR, or karyotype for newborns with suspected aneuploidy at birth.

Cell-free DNA analysis for noninvasive examination of trisomy.

Background: Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations.

Methods: In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing.

Assessment of fetal sex chromosome aneuploidy using directed cell-free DNA analysis.

Objective: To examine the performance of chromosome-selective sequencing of cell-free (cf) DNA in maternal blood for assessment of fetal sex chromosome aneuploidies.

Methods: This was a case-control study of 177 stored maternal plasma samples, obtained before fetal karyotyping at 11-13 weeks of gestation, from 59 singleton pregnancies with fetal sex chromosome aneuploidies (45,X, n = 49; 47,XXX, n = 6; 47,XXY, n = 1; 47,XYY, n = 3) and 118 with euploid fetuses (46,XY, n = 59; 46,XX, n = 59). Digital analysis of selected regions (DANSR™) on chromosomes 21, 18, 13, X and Y was performed and the fetal-fraction optimized risk of trisomy evaluation (FORTE™) algorithm was used to estimate the risk for non-disomic genotypes.

Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma.

Objective: To determine the effects of gestational age and maternal weight on percent fetal cell-free DNA (cfDNA) in maternal plasma and the change in fetal cfDNA amounts within the same patient over time.

Methods: The cfDNA was extracted from maternal plasma from 22 384 singleton pregnancies of at least 10 weeks gestation undergoing the Harmony(TM) Prenatal Test. The Harmony Prenatal Test determined fetal percentage via directed analysis of cfDNA.

Non-invasive prenatal testing with cell-free DNA: US physician attitudes toward implementation in clinical practice.

Objective: The aim of this study was to assess awareness, potential adoption, and current utilization of non-invasive prenatal testing (NIPT) analysis for common fetal aneuploidies among obstetricians.

Methods: A 36-item web-based survey was designed to assess the current practice of fetal aneuploidy screening and knowledge and utilization of NIPT for fetal trisomy. Practicing obstetricians in the United States were invited via email to participate in the survey.

Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population.

Objective: Evaluate noninvasive prenatal testing (NIPT) with cell-free DNA as a screening method for trisomies 21, 18, and 13 in an obstetrical clinical practice setting.

Methods: Observational study of pregnant women who underwent prenatal screening for fetal trisomy from 30 July 2012 to 1 December 2012. NIPT was offered to all patients in addition to first trimester combined screening (FTS).

Clinical utility and cost of non-invasive prenatal testing with cfDNA analysis in high-risk women based on a US population.

Objective: Evaluate the clinical and economic consequences of fetal trisomy 21 (T21) screening with non-invasive prenatal testing (NIPT) in high-risk pregnant women.

Methods: Using a decision-analytic model, we estimated the number of T21 cases detected, the number of invasive procedures performed, corresponding euploid fetal losses and total costs for three screening strategies: first trimester combined screening (FTS), integrated screening (INT) or NIPT, whereby NIPT was performed in high-risk patients (women 35 years or older or women with a positive conventional screening test). Modeling was based on a 4 million pregnant women cohort in the US.

The fetal fraction of cell-free DNA in maternal plasma is not affected by a priori risk of fetal trisomy.

Objective: To determine the relationship between a priori risk for fetal trisomy and the fraction of fetal cell-free DNA (cfDNA) in maternal blood.

Methods: A comparative analysis on fetal cfDNA amounts was performed in subjects stratified into a priori risk groups based on maternal age, prenatal screening results, or nuchal translucency measurement.

Results: Across the highest and lowest deciles within each group, there were no significant differences in the fetal cfDNA fraction.

Carrier testing for spinal muscular atrophy.

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care.

Prenatal carrier testing for fragile X: counseling issues and challenges.

Healthy women who carry a ''premutation'' in the FMR1 gene (or fragile X mental retardation protein) can pass on a further mutated copy of FMR1 to either male or female offspring, leading to fragile X syndrome (FXS). Premutation carriers do not have manifestations of FXS in cognitive deficits, behavioral abnormalities, or classic physical features, but are at increased risk for development of the ''fragile X-associated disorders'': premature ovarian insufficiency and fragile X-associated tremor and ataxia syndrome. When considering widespread prenatal carrier screening programs for fragile X, significant resources must be available for at-risk individuals, including counseling, accurate diagnostic options for fetal testing, and choice regarding continuation of a pregnancy.

The cost-effectiveness of prenatal screening for spinal muscular atrophy.

Objective: We sought to investigate the cost-effectiveness of prenatal screening for spinal muscular atrophy (SMA).

Study Design: A decision analytic model was created to compare a policy of universal SMA screening to that of no screening. The primary outcome was incremental cost per maternal quality-adjusted life year.

Nuchal translucency screening: how do women actually utilize the results?

Objective: To examine how women use the nuchal translucency (NT) risk adjustment in decision-making for invasive prenatal diagnosis.

Study Design: Retrospective cohort study of 1083 consecutive NT screening exams. A screen-positive test was defined as a risk > or = 1/300.

Attitudes toward prenatal screening and testing for Fragile X.

Purpose: Currently, the American Colleges of Medical Genetics and Obstetrics and Gynecology recommend screening in the prenatal setting only for individuals with specific family history indicators. Our aims were to study patient attitudes and psychologic impact of offering widespread screening for Fragile X in a prenatal setting.

Methods: Participants were recruited from pregnant women referred for "Prenatal Diagnosis Options" counseling by their primary provider in the first trimester of pregnancy.

Cost-effectiveness analysis of prenatal population-based fragile X carrier screening.

Objective: To investigate the cost-effectiveness of a widespread prenatal population-based fragile X carrier screening program.

Study Design: A decision tree was designed comparing screening versus not screening for the fragile X mental retardation protein 1 premutation in all pregnant women. Baseline values included a prevalence of fragile X mental retardation protein 1 premutations of 3.

Screening for single gene genetic disease.

The screening and directed testing for genetic disease caused by single gene mutations is an expanding part of the overall scheme of prenatal care. In addition to reproductive choice, carrier screening and fetal diagnostic testing afford the important opportunity for preparation of the family and the delivery site for the birth of a fetus with a known genetic disorder. Increasingly the primary care provider in pregnancy bears the burden of engaging patients in discussions regarding available genetic tests appropriate to their family or personal history, their ethnic group, and with every patient for a limited but growing number of diseases.

Complications of term pregnancies beyond 37 weeks of gestation.

Objective: To estimate when rates of pregnancy complications increase beyond 37 weeks of gestation.

Methods: We designed a retrospective, cohort study of all women delivered beyond 37 weeks of gestational age from 1992 to 2002 at a single community hospital. Rates of perinatal complications by gestational age were analyzed with both bivariate and multivariable analyses.

Meconium-stained amniotic fluid is associated with puerperal infections.

Objective: The purpose of this study was to determine whether meconium-stained amniotic fluid is associated with puerperal infection and whether the quality of the meconium is further associated with this risk.

Study Design: We designed a retrospective cohort study of all deliveries beyond 37 weeks gestational age from 1992 to 2002 at a single community hospital. Data were collected on rates of chorioamnionitis, endomyometritis, quality of amniotic fluid, and length of labor and analyzed with bivariate and multivariate analyses.

Rapid prenatal diagnosis in translocation carriers by interphase FISH with chromosome-specific subtelomere probes.

Interphase fluorescence in situ hybridization (FISH) analysis can provide rapid preliminary analysis of chromosome aneuploidy from direct amniocyte and chorionic villus sample (CVS) preparations. Typically, interphase FISH is used in screening for numerical abnormalities of chromosomes X, Y, 13, 18, and 21. More recently, FISH probe sets became available for the subtelomeric region of each chromosome, allowing screening for terminal chromosome rearrangements.