Technical Performance of a 430-Gene Preventative Genomics Assay to Identify Multiple Variant Types Associated with Adult-Onset Monogenic Conditions, Susceptibility Loci, and Pharmacogenetic Insights.

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.

Validation of a multiplex genotyping platform using a novel genomic database approach.

PURPOSE: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Past performance of assisted reproduction technologies as a model to predict future progress: a proposed addendum to Moore's law.

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 (<35 years old) and 294 years for the 41-42-year age group. The timeframe is shifted for the younger patients to an earlier date of 2027 if a subset of clinics with high implantation regression slopes and low variance is selected. The implications of these findings for infertility treatment and fertility preservation are discussed. Success after IVF has steadily improved. Data from US-based clinics are annually collected by the Society for Assisted Reproductive Technologies (SART; www.sart.org). Through SART, individual clinic's outcomes may be assessed. Although live birth and pregnancy are considered the gold standard of success, the investigators took the approach that those outcomes are often biased due to transfer of multiple embryos. The present analysis was therefore performed on individual embryos, by using the implantation rate to compare national and individual clinic datasets. National implantation rates show a linear increase from year to year ranging between 0.3% and 1.5% for patients aged <43 years. We postulate that this linear trend can be traced back to 1985 even though statistical analysis could only be applied to the implantation data from 2003-2010. We expect that this annual incline is partly technology driven. This is an intriguing effect also seen in the computer industry where there has been a doubling of computer speed and memory for the past 47 years, a phenomenon anticipated by Moore's law. We predict that the annual increase in implantation will also continue as new technologies become available. Based on current trends, the length of time for 100% implantation rates was calculated. Time to achieving 100% implantation varied between 43 years (AD 2053) for the youngest age group (<35 years old) to 294 years for women 41-42 years old. Some clinics may report a perfect success earlier than others. However, implantation does not guarantee birth.