Screening system and method for determining a presence and an assessment score of cell-free DNA fragments
Inventors
LENCH, Nicholas • HURLES, Matt • MCGONIGLE, John • Martin, Alan • DRURY, Suzanne
Assignees
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Publication Number
US-11869630-B2
Publication Date
2024-01-09
Expiration Date
Abstract
A prenatal screening system includes a wet-laboratory arrangement and a data processing arrangement to exchange instructions and data with the wet-laboratory arrangement. The data processing arrangement includes a database arrangement storing genetic information accessible to one or more algorithms executable on the data processing arrangement. The wet-laboratory arrangement collects one or more maternal blood samples from a pregnant mother. The wet-laboratory arrangement isolates free fetal DNA fragments present in cell-free DNA derived from plasma of the one or more maternal blood samples. The isolation utilizes baits based upon coordinates of cell-free fetal DNA fragment specific end-points, and the data processing arrangement analyses the isolated free fetal DNA and compares with one or more DNA templates stored in the data processing arrangement for determining an occurrence of one or more biological characteristics of fetal DNA present in the one or more maternal blood samples.
Core Innovation
The invention provides a non-invasive prenatal screening system for determining a presence of cell-free DNA fragments in a biological sample comprising one or more maternal blood samples from a pregnant mother. The wet-laboratory arrangement enriches cell free fetal DNA fragments present in cell-free DNA derived from plasma of the one or more maternal blood samples, and the enriched fragments start within a nucleosome and have a shorter nucleic acid base count than an average length nucleic acid base count of cell-free DNA in the one or more maternal blood samples.
The fragments are sequenced, and a data processing arrangement compares information representative of the sequenced DNA fragments against information stored in a genomic database arrangement to provide an assessment score with respect to the biological sample. The assessment score is associated with one or more stochastic ratings associated with the sequenced DNA fragments.
To reduce a stochastic and/or systemic uncertainty present in the assessment score, the system applies a modification to the one or more stochastic ratings using secondary information provided to the screening system. In particular embodiments, the secondary information includes genome locality score, sequence error score, patient modifier score, and mosaicism detection score.
In further embodiments, the wet-laboratory arrangement processes maternal blood samples and generates cell-free DNA readout data including ligation of nucleic acid base molecular barcodes to fragments prior to amplifying and sequencing. The screening system may also use enrichment baits targeting specific end-points of cell-free fetal DNA based on coordinates, and molecular barcodes implemented as an n-mer with n between 3 and 100.
Claims Coverage
The document includes two independent claims directed to a screening system and a method using the screening system. Across these independent claims, the coverage centers on nucleosome-starting, shorter-than-average-length cell-free fetal DNA enrichment with sequencing, genomic database comparison to provide an assessment score, and uncertainty reduction by modifying stochastic ratings using secondary information.
Nucleosome-starting shorter-than-average-length cffDNA enrichment and sequencing
Enriching cell free fetal DNA fragments that start within a nucleosome and have a shorter nucleic acid base count than an average length nucleic acid base count of cell-free DNA in one or more maternal blood samples, and sequencing the cell-free DNA fragments.
Genomic database comparison to provide an assessment score
Comparing information representative of the sequenced DNA fragments against information stored in a genomic database arrangement to provide an assessment score with respect to the biological sample.
Modification of stochastic ratings using secondary information to reduce uncertainty
Applying a modification to one or more stochastic ratings associated with the information representative of the sequenced DNA fragments using secondary information provided to the screening system to reduce a stochastic and/or systemic uncertainty present in the assessment score.
Method processing with corresponding screening-system operation and uncertainty-modified assessment
Processing a biological sample comprising one or more maternal blood samples in a wet-laboratory arrangement configured to enrich nucleosome-starting, shorter nucleic-acid-count cell free fetal DNA fragments and sequence the DNA fragments; comparing sequenced-fragment information against genomic database information to provide an assessment score; and applying a modification to one or more stochastic ratings using secondary information to reduce a stochastic and/or systemic uncertainty present in the assessment score.
Overall, claim coverage is anchored in nucleosome-starting and shorter-than-average-length cffDNA enrichment from plasma-derived maternal blood cell-free DNA, sequencing followed by comparison to information in a genomic database arrangement to generate an assessment score, and modifying stochastic ratings with secondary information to reduce stochastic and/or systemic uncertainty.
Stated Advantages
Reduce a stochastic and/or systemic uncertainty present in the assessment score.
Documented Applications
Non-invasive prenatal screening by determining a presence of cell-free DNA fragments in maternal blood during pregnancy.
Screening to provide an assessment score with respect to a biological sample based on sequenced cell-free DNA fragment information compared to genomic database information.
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