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DNA-based screening in individuals without known risk factors potentially identifies those who may benefit from genetic counseling, early medical interventions, and/or avoidance of late or missed diagnoses. While not currently in widespread usage, technological advances in genetic analysis overcome barriers to access by enabling less labor-intensive and more cost-efficient means to discover variants of clinical importance. This study describes the technical validation of a 430-gene next-generation sequencing based assay, GeneCompassTM, indicated for the screening of healthy individuals in the areas of actionable health risks, pharmaceutical drug response, and wellness traits. The test includes genes associated with Mendelian disorders and genetic susceptibility loci, encompassing 14 clinical areas and pharmacogenetic variants. The custom-designed target enrichment capture and bioinformatics pipelines interrogate multiple variant types, including single nucleotide variants, insertions/deletions (indels), copy number variants, and functional haplotypes (star alleles), including tandem alleles and structural variants. Validation was performed against reference DNA from three sources: 1000 Genomes Project (n = 3), Coriell biobank (n = 105), and previously molecularly characterized biological specimens: blood (n = 15) and saliva (n = 11). Analytical sensitivity and specificity for single nucleotide variants (SNVs) were 97.57% and 99.99%, respectively, and for indels were 74.57% and 97.34%, respectively. This study demonstrates the validity of an NGS assay for genetic screening and the broadening of access to preventative genomics.

BackgroundRapid and easy COVID-19 diagnostic testing is essential to controlling the pandemic and facilitating safe resumption of clinical care, employment and other social activities.MethodsThis study was conducted to validate an self-administrable saliva-based RT-qPCR test for the SARS-CoV2 virus under controlled laboratory conditions (analytical validation) according to federal guidance. An additional clinical study assessed positive (n = 34) and negative (n = 57) nasopharyngeal swab samples collected contemporaneously with saliva samples. Assessments for analytical specificity, sensitivity, cross reactivity and sample stability to simulate shipping conditions were conducted.ResultsPositive and negative agreement with third-party laboratory results were reported as 97.1% and 96.5–98.2%, respectively. Limit of detection was established at 5 copies/µL. Stability through simulated shipping conditions found 100% concordance up to 56 hours after collection. Discussion: These data validate a self-collected saliva-based COVID-19 RT-qPCR assay that performs comparably well to an assay of health care-provider administered nasopharyngeal swab samples. Accordingly, the United States Food and Drug Administration granted emergency use authorization in June 2020. Use of the saliva-based assay overcomes barriers to the necessary widespread testing, including strained health care resources, supply chain disruptions of laboratory materials, testing and protective equipment and exposure risks due to close interpersonal contact.

The ultimate goal of IVF is to achieve healthy, single, live births following each single-embryo transfer. A timeline for this eventuality has never been defined. National implantation rates from 2003-2010 provided by the Society for Assisted Reproductive Technologies (SART) in the USA were evaluated. Regression analysis was applied to the annual trends. A high correlation was noted showing a linear increase from year to year ranging between 0.3% and 1.5% when maternal age was not higher than 42. This relationship can be retrospectively applied to earlier SART data reports. This incline may be partly technology driven and resembles Moore's law, which describes annual improvements in microchip performance. Based on the assumption that technology will continue to drive progress, the length of time required to reach 100% implantation was calculated. The interval varied between 43 years (AD 2053) for the youngest age group (

Technological advances now allow for multiplex platforms to simultaneously test many genetic conditions. Typically, such platforms are validated by assaying samples with known genotypes and/or phenotypes and/or with synthetic plasmids; however, these methods have limitations and with the inclusion of rarer diseases and mutations, we can no longer rely solely on them. We used a novel genomic database to validate an expanded genetic carrier screening platform. Our expanded carrier screening assay uses the Illumina Infinium iSelect HD Custom genotyping platform to test for 213 genetic diseases by assaying 1,663 pathogenic mutations. We leveraged two Coriell Institute biorepositories for validation: the Subcollection of Heritable Diseases and the 1000 Genomes Project. We measured 12,394 mutation observations in 206 samples, resulting in 246 true positives, 12,147 true negatives, 1 false positive, and no false negatives. Results demonstrated high sensitivity (99.99%) and specificity (99.99%). We successfully validated our platform with two biorepositories, demonstrating high sensitivity and specificity. The 1000 Genomes Project samples provided both positive and negative validation for mutations in genes not available through other biorepositories, expanding the depth of validated variants. We recommend including samples from the 1000 Genomes Project in the validation of future multiplex testing platforms. Genet Med advance online publication 30 July 2015

Technological advances now allow for multiplex platforms to simultaneously test many genetic conditions. Typically, such platforms are validated by assaying samples with known genotypes and/or phenotypes and/or with synthetic plasmids; however, these methods have limitations and with the inclusion of rarer diseases and mutations, we can no longer rely solely on them. We used a novel genomic database to validate an expanded genetic carrier screening platform.Our expanded carrier screening assay uses the Illumina Infinium iSelect HD Custom genotyping platform to test for 213 genetic diseases by assaying 1,663 pathogenic mutations. We leveraged two Coriell Institute biorepositories for validation: the Subcollection of Heritable Diseases and the 1000 Genomes Project.We measured 12,394 mutation observations in 206 samples, resulting in 246 true positives, 12,147 true negatives, 1 false positive, and no false negatives. Results demonstrated high sensitivity (99.99%) and specificity (99.99%).We successfully validated our platform with two biorepositories, demonstrating high sensitivity and specificity. The 1000 Genomes Project samples provided both positive and negative validation for mutations in genes not available through other biorepositories, expanding the depth of validated variants. We recommend including samples from the 1000 Genomes Project in the validation of future multiplex testing platforms.Genet Med advance online publication 30 July 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.101.

e13105 Background: Diagnosis of hereditary cancer syndromes involves time-consuming comprehensive clinical and laboratory work-up, however, timely and accurate diagnosis is pivotal to the clinical management of cancer patients. Germline genetic testing has shown to facilitate the diagnostic process, allowing for identification and management of individuals at risk for inherited cancers. However, the laboratory diagnostics process requires not only development and validation of comprehensive gene panels to improve diagnostic yields, but a quality driven workflow including an end-to-end bioinformatics pipeline, and a robust process for variant classification. We will present a gene panel for the evaluation of hereditary cancer syndromes, conducted utilizing our novel end-to-end workflow, and validated in the CLIA-approved environment. Methods: A targeted Next-Generation Sequencing (NGS) panel consisting of 130 genes, including exons, promoters, 5’-UTRs, 3’-UTRs and selected introns, was designed to include genes associated with hereditary cancers. The assay was validated using samples from the 1000 genomes project and samples with known pathogenic variants. Elements software was utilized for end-to-end bioinformatic process ensuring adherence with the CLIA quality standards, and supporting manual curation of sequence variants. Results: Preliminary data from our current panel of genes associated with hereditary cancer syndromes revealed high sensitivity, specificity, and positive predictive value. Accuracy was confirmed by analysis of known SNVs, indels, and CNVs using 1000 Genomes and samples carrying pathogenic variants. The bioinformatics software allowed for an end-to-end quality controlled process of handling and analyzing of the NGS data, showing applicability for a clinical laboratory workflow. Conclusions: We have developed a comprehensive and accurate genetic testing process based on an automated and quality driven bioinformatics workflow that can be used to identify clinically important variants in genes associated with hereditary cancers. It's performance allows for implementation in the clinical laboratory setting.

Diagnosis of embryos for chromosome abnormalities, i.e. aneuploidy screening, has been invigorated by the introduction of microarray-based testing methods allowing analysis of 24 chromosomes in one test. Recent data have been suggestive of increased implantation and pregnancy rates following microarray testing. Preimplantation genetic diagnosis for infertility aims to test for gross chromosome changes with the hope that identification and transfer of normal embryos will improve IVF outcomes. Testing by some methods, specifically single-nucleotide polymorphism (SNP) microarrays, allow for more information and potential insight into parental origin of aneuploidy and uniparental disomy. The usefulness and validity of reporting this information is flawed. Numerous papers have shown that the majority of meiotic errors occur in the egg, while mitotic errors in the embryo affect parental chromosomes at random. Potential mistakes made in assigning an error as meiotic or mitotic may lead to erroneous reporting of results with medical consequences. This study's data suggest that the bioinformatic cleaning used to 'fix' the miscalls that plague single-cell whole-genome amplification provides little improvement in the quality of useful data. Based on the information avail- able, SNP-based aneuploidy screening suffers from a number of serious issues that must be resolved. RBMOnline

range from ancient-and-common polymorphisms with minimal effects to recent-and-rare mutations predicted to have larger effects on the phenotype. Applying NGS and IBD analysis using nuclear families, we were able to identify 5 candidate endometriosis regions that show excess genetic burden. A more complete picture of the genetics of endometriosis is likely to emerge as additional WGS data are analyzed. Supported by: Juneau Biosciences.