Abstract: Disclosed is a method of determining whether a human subject is not a carrier of spinal muscular atrophy (SMA). This method includes the steps of (i) collecting a genomic deoxyribonucleic acid (DNA) sample from a human subject; (ii) screening the genomic DNA sample to determine the human subject's copy number of survival of motor neuron 1 (SMN1) gene and whether one of the copies of the SMN1 gene is positive for a polymorphism associated with non-carriers of SMA having two copies of the SMN1 gene; and (iii) determining the human subject as not a carrier of SMA if the human subject includes two copies of the SMN1 gene with one of those copies being positive for the polymorphism. Also disclosed is a method of determining whether an individual has a decreased risk of being a carrier of spinal muscular atrophy (SMA), where the individual is identified to have a decreased risk of being a carrier of SMA when the individual has two copies of the SMN1 gene with one of those copies being positive for the polymorphism.

Abstract: The invention provides methods, apparatuses, and compositions for high-throughput amplification sequencing of specific target sequences in one or more samples. In some aspects, barcode-tagged polynucleotides are sequenced simultaneously and sample sources are identified on the basis of barcode sequences. In some aspects, sequencing data are used to determine one or more genotypes at one or more loci comprising a causal genetic variant. In some aspects, systems and methods of detecting genetic variation are provided.

Abstract: High-fidelity, high-throughput nucleic acid sequencing enables healthcare practitioners and patients to gain insight into genetic variants and potential health risks. However, previous methods of nucleic acid sequencing often introduce sequencing errors (for example, mutations that arise during the preparation of a nucleic acid library, during amplification, or sequencing). Provided herein are methods and compositions for sequencing nucleic acids. Further provided are methods of identifying an error in a nucleic acid sequence.

Abstract: Provided are methods and compositions for enriching cfDNA fragments from a biological fluid sample. A biological fluid sample, such as a urine sample, is collected and, in certain examples, pretreated before enrichment of the cfDNA. For the pretreatment, the sample is centrifuged to remove large cells and large cellular debris. As part of the pretreatment, the sample is also cleared of additional large cellular debris and excess volume by subjecting the sample to anion exchange chromatography and eluting bound DNA. Following any pretreatment of the sample, different concentrations an alcoholic solution are used—along with a mixture of DNA-binding particles and a chaotropic agent—to enrich the sample with cfDNA fragments having different sizes. For example, a biological sample can be enriched with small cfDNA fragments less than about 100 base pairs in length or large cfDNA fragments greater than about 100 base pairs in length.

Abstract: Direct targeted sequencing (DTS) methods and a hidden Markov model (HMV) can be used to call the copy number of a segment of interest within a region of interest. Described herein are methods for calling a copy number variant or a copy number variant abnormality using an HMM, and methods for determining a copy number based on a copy number likelihood model, in a test sequencing library that has be sequenced using DTS methods. Also described herein are methods for determining a copy number of a segment, including accounting for spurious capture probes that may arise from the DTS methods.

Abstract: A system and method for determining a respective carrier status of an individual is provided. In one implementation, a method includes training a neural network model based on predetermined information related to at least one genetic variant and determining the respective carrier status based on a normalized read depth for the gene in a genome of the individual and allele dosage data for the gene using a machine learning algorithm. The method is configured to receive, as inputs, the normalized read depth and allele dosage data, and output the respective carrier status of the individual for the at least one genetic variant. In another implementation a system includes a recurrent neural network. The recurrent neural network includes a plurality of long short-term memory (LSTM) network cells linked sequentially in the recurrent neural network, a plurality of layers of long short-term memory (LSTM) network cells; and a fully connected sigmoid module.

Abstract: Disclosed herein are high-throughput sample processing systems and waste management systems, and methods of using the same.

Abstract: The present disclosure relates to methods for detecting unique genetic signatures derived from markers such as, for example, mutations, somatic or germ-line, in nucleic acids obtained from biological samples. The sensitivity of the methods provides for detection of mutations associated with a disease, e.g., cancer mutations, or with inherited disease, e.g., an autosomal recessive disease, in a noninvasive manner at ultra-low proportions of sequences carrying mutations to sequences carrying normal, e.g., non-cancer sequences, or a reference sequence, e.g., a human reference genome.

Abstract: Described herein are methods of assessing a sample-specific performance of a copy number variant model, a method for determining a copy number of an interrogated segment within a region of interest, and a method for determining a copy number variant abnormality within a region of interest. Sample-specific performance of the copy number variant caller is assessed by parameterizing a copy number variant model base on sequencing reads from a test sample, generating synthetic copy number variants using the sequencing read from the test sample, and calling the number of copies in the synthetic copy number variants using the copy number variant model and the sample-specific parameters. Calling a number of copies of an interrogated segment can include parameterizing a hidden Markov model using an analytic first derivative gradient and second derivative Hessian of one or more parameters in a copy number likelihood model.

Abstract: Reagent delivery systems, which can include a reagent trough and a pump system, are useful for delivering liquids to a laboratory workbench. Processing samples on the laboratory workbench can result in a large amount of liquid waste. Described herein are reagent troughs, pump systems, reagent delivery systems, waste management systems, and methods of using the same.

Abstract: The method described herein combines experimental and analytical approaches to resolve the structure of a genomic region in the genome of a subject whose sequence is highly homologous to one or more other regions of the genome. For example, the genomic region may be a gene and the highly homologous other region may be a pseudogene. The method involves independent alignment, pairing, and analysis of sequence reads from the genomic region and the highly homologous other region to identify genetic variation. Also described herein is a computer-assisted method for such methods.

Abstract: Reagent delivery systems, which can include a reagent trough and a pump system, are useful for delivering liquids to a laboratory workbench. Processing samples on the laboratory workbench can result in a large amount of liquid waste. Described herein are reagent troughs, pump systems, reagent delivery systems, waste management systems, and methods of using the same.

Abstract: High-fidelity, high-throughput nucleic acid sequencing enables healthcare practitioners and patients to gain insight into genetic variants and potential health risks. However, previous methods of nucleic acid sequencing often introduces sequencing errors (for example, mutations that arise during the preparation of a nucleic acid library, during amplification, or sequencing). Provided herein are methods and compositions for sequencing nucleic acids. Further provided are methods of identifying an error in a nucleic acid sequence.

Abstract: Described herein are methods directed to determining the carrier status or genotype of a subject. Described herein is a method that combines experimental and computational approaches to resolve the structure of genomic loci (i.e., the genotype) whose sequences are highly homologous to other sequences in the genome. In particular, the determination of carrier status and/or copy number of a gene in a subject, wherein the gene has a corresponding highly homologous homolog, e.g., gene or pseudogene, utilizes Next Generation Sequencing. Also described herein is a computer-assisted method for such determinations.

Abstract: Methods for determining a respective carrier status of an individual are disclosed. In some examples, the method includes determining the respective carrier status based on copy number data for a gene in a genome of the individual and SNP data for the gene using a machine learning algorithm. In some examples, the machine learning algorithm is configured to receive, as inputs, the copy number data and the SNP data, and output the respective carrier status of the individual.

Abstract: Disclosed is a method of determining whether a human subject is not a carrier of spinal muscular atrophy (SMA). This method includes the steps of (i) collecting a genomic deoxyribonucleic acid (DNA) sample from a human subject; (ii) screening the genomic DNA sample to determine the human subject's copy number of survival of motor neuron 1 (SMN1) gene and whether one of the copies of the SMN1 gene is positive for a polymorphism associated with non-carriers of SMA having two copies of the SMN1 gene; and (iii) determining the human subject as not a carrier of SMA if the human subject includes two copies of the SMN1 gene with one of those copies being positive for the polymorphism. Also disclosed is a method of determining whether an individual has a decreased risk of being a carrier of spinal muscular atrophy (SMA), where the individual is identified to have a decreased risk of being a carrier of SMA when the individual has two copies of the SMN1 gene with one of those copies being positive for the polymorphism.

Abstract: High-fidelity, high-throughput nucleic acid sequencing enables healthcare practitioners and patients to gain insight into genetic variants and potential health risks. However, previous methods of nucleic acid sequencing often introduce sequencing errors (for example, mutations that arise during the preparation of a nucleic acid library, during amplification, or sequencing). Provided herein are methods and compositions for sequencing nucleic acids. Further provided are methods of identifying an error in a nucleic acid sequence.

Abstract: The present disclosure relates to methods for detecting unique genetic signatures derived from markers such as, for example, mutations, somatic or germ-line, in nucleic acids obtained from biological samples. The sensitivity of the methods provides for detection of mutations associated with a disease, e.g., cancer mutations, or with inherited disease, e.g., an autosomal recessive disease, in a noninvasive manner at ultra-low proportions of sequences carrying mutations to sequences carrying normal, e.g., non-cancer sequences, or a reference sequence, e.g., a human reference genome.

Abstract: The present disclosure relates to processes for determining the number of nucleic acid repeats in a DNA fragment comprising a nucleic acid repeat region. One example method may include receiving DNA size and abundance data generated by resolving DNA amplification products. A set of low-pass data may be generated by applying a low-pass filter to the DNA size and abundance data and a set of band-pass data may be generated by applying a band-pass filter to the DNA size and abundance data. A peak of the DNA size and abundance data representative of a number of nucleic acid repeats in the DNA may be identified based on peaks identified from the low-pass data and the band-pass data.

Abstract: The present disclosure relates to methods for detecting unique genetic signatures derived from markers such as, for example, mutations, somatic or germ-line, in nucleic acids obtained from biological samples. The sensitivity of the methods provides for detection of mutations associated with a disease, e.g., cancer mutations, or with inherited disease, e.g., an autosomal recessive disease, in a noninvasive manner at ultra-low proportions of sequences carrying mutations to sequences carrying normal, e.g., non-cancer sequences, or a reference sequence, e.g., a human reference genome.