Methods and systems for genetic analysis

Patent metadata

Field	Value
Publication number	US-11976326-B2
Application number	US-202318178764-A
Country	US
Kind code	B2
Filing date	Mar 6, 2023
Priority date	Jan 17, 2013
Publication date	May 7, 2024
Grant date	May 7, 2024

Abstract

This disclosure provides systems and methods for sample processing and data analysis. Sample processing may include nucleic acid sample processing and subsequent sequencing. Some or all of a nucleic acid sample may be sequenced to provide sequence information, which may be stored or otherwise maintained in an electronic storage location. The sequence information may be analyzed with the aid of a computer processor, and the analyzed sequence information may be stored in an electronic storage location that may include a pool or collection of sequence information and analyzed sequence information generated from the nucleic acid sample. Methods and systems of the present disclosure can be used, for example, for the analysis of a nucleic acid sample, for producing one or more libraries, and for producing biomedical reports. Methods and systems of the disclosure can aid in the diagnosis, monitoring, treatment, and prevention of one or more diseases and conditions.

First claim

What is claimed is:

1. A method for analyzing nucleic acid sample(s) of a subject, comprising:
(a) generating at least a first subset of nucleic acid molecules and a second subset of nucleic acid molecules from one or more nucleic acid samples of a subject, wherein:
(i) the first subset of nucleic acid molecules is selectively enriched with pulldown probes that selectively enrich for the genomic feature consisting of an exome as compared to pulldown probes that do not enrich for an exome, and
(ii) the second subset of nucleic acid molecules is selectively enriched with pulldown probes that selectively enrich for a genomic feature selected from the group consisting of: (i) a plurality of genes encoding known disease traits, (ii) a plurality of genes encoding known drug traits, (iii) a plurality of genes encoding known biomedically interpretable variants, and any combination thereof, as compared to pulldown probes that do not selectively enrich for the genomic features, wherein the plurality of genes of the genomic feature comprises a plurality of polymorphisms that are based on or extracted from one or more databases and are observed in a population of one or more samples;

(b) subjecting (i) the first subset of nucleic acid molecules to a first assay to yield a first result comprising a first nucleic acid sequence, and (ii) the second subset of nucleic acid molecules to a second assay to yield a second result comprising a second nucleic acid sequence;
(c) combining, with the aid of a computer processor, the first result and the second result to generate an output comprising a consensus sequence from the first nucleic acid sequence and the second nucleic acid sequence; and
(d) generating one or more biomedical outputs that include biomedical information of the subject, which biomedical information is indicative of the output of (c), thereby analyzing nucleic acid sample(s) of the subject, wherein:
(1) the one or more biomedical outputs: (i) suggest, select, designate, recommend, or otherwise determine a course of treatment and/or prevention of a disease or condition, or (ii) recommend modifying or continuing one or more therapies for a disease or condition,
(2) the disease or condition comprises a cancer, and
(3) the course of treatment or the one or more therapies comprises a cancer vaccine.

2. The method of claim 1 , wherein the cancer comprises a recurrent and/or refractory cancer.

3. The method of claim 1 , wherein the cancer comprises a sarcoma, a carcinoma, a lymphoma, or a leukemia.

4. The method of claim 1 , wherein the cancer vaccine comprises a therapeutic vaccine or a prophylactic vaccine.

5. The method of claim 1 , further comprising predicting, diagnosing, and/or prognosing a status or outcome of a disease or a condition in the subject based on the one or more biomedical outputs.

6. The method of claim 5 , wherein the predicting, diagnosing, and/or prognosing a status or outcome of a disease in the subject comprises diagnosing a disease or condition, identifying a disease or condition, determining the stage of a disease or condition, assessing the risk of a disease or condition, assessing the risk of disease recurrence, assessing the efficacy of a drug, assessing risk of an adverse drug reaction, predicting optimal drug dosage, predicting drug resistance, or a combination thereof, wherein the disease or condition comprises cancer.

7. The method of claim 6 , wherein the cancer comprises a recurrent and/or refractory cancer.

8. The method of claim 6 , wherein the cancer comprises a sarcoma, a carcinoma, a lymphoma, or a leukemia.

9. The method of claim 1 , wherein modifying one or more therapies comprises administering, initiating, reducing, increasing, and/or terminating one or more therapies.

10. The method of claim 1 , wherein the first subset of nucleic acid molecules and the second subset of nucleic acid molecules are derived from the same nucleic acid sample.

11. The method of claim 10 , wherein the nucleic acid sample is derived from a sample selected from the group consisting of a tissue biopsy, blood, plasma, and a blood fraction.

12. The method of claim 1 , wherein the first subset of nucleic acid molecules and the second subset of nucleic acid molecules are derived from two or more different nucleic acid samples.

13. The method of claim 12 , wherein the two or more different nucleic acid samples are collected over two or more time points.

14. The method of claim 12 , wherein the first subset of nucleic acid molecules is derived from a sample selected from the group consisting of a tissue biopsy, blood, plasma, and a blood fraction.

15. The method of claim 12 , wherein the second subset of nucleic acid molecules is derived from a sample selected from the group consisting of a tissue biopsy, blood, plasma, and a blood fraction.

16. The method of claim 1 , wherein the first subset of nucleic acid molecules and/or second subset of nucleic acid molecules comprise nucleic acid molecules selected from the group consisting of DNA, RNA, DNA/RNA hybrids, or cDNA derived from RNA.

17. The method of claim 1 , wherein the exome comprises: (i) exons, (ii) untranslated regions (UTRs), and (iii) one or more splice sites, one or more intronic regions, one or more regulatory regions, or a combination thereof.

18. The method of claim 1 , wherein the plurality of polymorphisms comprises one or more of insertions, deletions, structural variant junctions, variable length tandem repeats, single nucleotide mutations, or a combination thereof.

19. The method of claim 1 , wherein the plurality of genes encoding known biomedically interpretable variants are selected from the group consisting of: (i) p53 mutations, (ii) Rb mutations, (iii) cell cycle regulators, (iv) cell cycle receptors, (v) cell cycle kinases, (vi) genes associated with cancer, and (vii) a combination thereof.

20. The method of claim 1 , wherein the first subset of nucleic acid molecules and/or the second subset of nucleic acid molecules is generated with the aid of (i) a hybridization reaction, or (ii) a differential amplification based on one or more genomic region features of the one or more nucleic acid samples.

21. The method of claim 1 , wherein the combining in (c) comprises combining the first nucleic acid sequence and the second nucleic acid sequence using: (i) a precedence rule that uses one or more of genomic context(s) or assay(s) to resolve discordances between two or more sequencing data sets, or (ii) at least one of quality and read coverage metrics to resolve one or more discordant genotypes.

22. The method of claim 1 , wherein the first subset of nucleic acid molecules and the second subset of nucleic acid molecules are subjected to the first assay and the second assay respectively in: (i) separate pools, or (ii) a combined pool.

Assignees

• Personalis Inc

Inventors

• Bartha Gabor T
• Chandratillake Gemma
• Chen Richard
• Garcia Sarah
• Lam Hugo Yu Kor
• Luo Shujun
• Pratt Mark R
• West John

Classifications

• C12Q1/6874 Primary

  involving nucleic acid arrays, e.g. sequencing by hybridisation · CPC title

• C12Q1/6806

  Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay (C12Q1/6804 takes precedence) · CPC title

• G16B20/00

  ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations · CPC title

• G16B20/10

  Ploidy or copy number detection · CPC title

• G16B20/20

  Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection · CPC title