Methods and systems for genetic analysis

12084,717

18/312710

May 05, 2023

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.

Personalis, Inc. (Menlo Park, CA, US)

PERSONALIS, INC. (Fremont, CA, US)

1. A method for analyzing nucleic acid samples obtained from a subject, comprising: (a) generating a first subset of nucleic acid molecules from a first nucleic acid sample obtained from a tumor sample of the subject; (b) conducting a first sequencing assay on the first subset of nucleic acid molecules to yield a first result comprising a first nucleic acid sequence, wherein the first sequencing assay comprises whole genome sequencing; (c) generating a second subset of nucleic acid molecules from a second nucleic acid sample of the subject by contacting the second nucleic acid sample with a plurality of pulldown probes, wherein: (i) the plurality of pulldown probes comprises 10 or more pulldown probes with different sequences; (ii) the plurality of pulldown probes hybridizes to a genomic region feature comprising a plurality of polymorphisms that are based on or extracted from one or more databases of polymorphisms, observed in a population of one or more samples, or a combination thereof; and (iii) the first nucleic acid sample is obtained from the subject at a first time point and the second nucleic acid sample is obtained from the subject at a second time point; (d) conducting a second sequencing assay on the second subset of nucleic acid molecules to yield a second result comprising a second nucleic acid sequence, wherein the second sequencing assay comprises sequencing by synthesis; (e) combining, with the aid of a computer processor, the first result and the second result, thereby analyzing the nucleic acid samples; and (f) generating a biomedical report that includes biomedical information of the subject, wherein the biomedical information identifies the presence or absence of the plurality of polymorphisms identified by the second result.

2. The method of claim 1 , further comprising: (i) using the plurality of pulldown probes to generate an additional subset of nucleic acid molecules from an additional nucleic acid sample isolated from an additional sample obtained from the subject at a third time point that is different from the first or second time point; (ii) conducting a third sequencing assay on the additional subset of nucleic acid molecules from the additional nucleic acid sample to yield a third result comprising a third nucleic acid sequence, wherein the third sequencing assay comprises sequencing by synthesis; and (iii) generating a biomedical report that includes biomedical information of the subject, wherein the biomedical information identifies the presence or absence of the plurality of polymorphisms identified by the second result or the third result.

3. The method of claim 2 , wherein the biomedical information of the subject is predictive, prognostic, or diagnostic of one or more biomedical features selected from the group consisting of disease state, efficacy of a drug therapy, prediction of optimal drug dosage, recommendation of one or more therapies, and recommendation of a course of treatment of a disease.

4. The method of claim 1 , wherein the biomedical information of the subject is predictive, prognostic, or diagnostic of one or more biomedical features selected from the group consisting of disease state, efficacy of a drug therapy, prediction of optimal drug dosage, recommendation of one or more therapies, and recommendation of a course of treatment of a disease.

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

6. The method of claim 1 , wherein the plurality of polymorphisms is in a set of genes with known biomedically interpretable variants.

7. The method of claim 6 , wherein the set of genes with known biomedically interpretable variants comprises a plurality of genes or variants associated with cancer.

8. The method of claim 7 , wherein the biomedically interpretable variants associated with cancer 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.

9. The method of claim 1 , wherein the plurality of pulldown probes comprises 40 or more pulldown probes.

10. The method of claim 1 , wherein the plurality of pulldown probes comprises 50 or more pulldown probes.

11. The method of claim 1 , wherein the plurality of pulldown probes comprises 100 or more pulldown probes.

12. The method of claim 1 , wherein the plurality of pulldown probes comprises 500 or more pulldown probes.

13. The method of claim 1 , wherein the plurality of pulldown probes comprises 1000 or more pulldown probes.

14. The method of claim 1 , wherein the plurality of pulldown probes is conjugated to beads.

15. The method of claim 1 , further comprising comparing the first result and the second result.

16. The method of claim 9 , wherein the second nucleic acid sample is isolated from a blood sample.

17. The method of claim 2 , wherein the additional sample comprises a plasma sample.

18. The method of claim 1 , wherein the whole genome sequencing produces at least 750,000,000 sequencing reads.

19. The method of claim 1 , wherein the one or more databases comprise one or more proprietary databases or one or more publicly available databases.

20. The method of claim 1 , wherein the second time point is later than the first time point.

21. The method of claim 2 , wherein the third time point is later than the first time point and/or the second time point.

22. The method of claim 2 , further comprising: (1) repeating the third sequencing assay one or more times on one or more subsequent samples to yield an additional result comprising a fourth nucleic acid sequence; and (2) generating an additional biomedical report that includes biomedical information of the subject, wherein the biomedical information identifies the presence or absence of the plurality of polymorphisms identified by the additional result.

23. The method of claim 16 , wherein the pulldown probes comprise between about 10 to about 500 nucleotides.

24. The method of claim 23 , wherein the plurality of pulldown probes is conjugated to beads.

25. The method of claim 24 , wherein mean sequencing size of the second sequencing assay is at least about 100 base pairs.

26. The method of claim 25 , wherein the plurality of pulldown probes hybridizes to at least two genomic region features that are within, near, or spanning a gene of interest.

27. The method of claim 26 , wherein percent error rate of the second sequencing reaction is less than about 0.001%.

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