Determining amounts of contributor-derived nucleic acids of a mixed sample (3+ genetically distinct genomic contributors) of a transplant recipient
A computer-implanted system quantifies contributor-derived nucleic acids in a graft recipient's sample to address the challenge of accurately determining their amounts, improving graft monitoring and rejection assessment.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- CAREXDX INC
- Filing Date
- 2026-04-23
- Publication Date
- 2026-07-17
AI Technical Summary
Existing methods are inadequate for accurately determining the amount of contributor-derived nucleic acids from multiple sources in a biological sample, which is crucial for monitoring graft status and assessing rejection risk.
A computer-implanted system and method to quantify contributor-derived nucleic acids from two or more different contributors in a graft recipient's sample, enabling precise estimation of their percentages.
Enables accurate monitoring of graft status and risk assessment by quantifying nucleic acids from multiple contributors, enhancing the detection of graft rejection.
Smart Images
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Abstract
Description
EP4639549 (54) Title: Determining the Amount of Contributor-Derived Nucleic Acids in a Mixed Sample (Different Genomic Contributors on 3+ Genes) of a Graft Recipient (57) Abstract: This document discloses a computer-implanted system, kit, and method for determining the amount of contributor-derived nucleic acids in a biological sample from a graft recipient containing nucleic acids from two or more different contributors on two or more genes. The determined amount of contributor-derived nucleic acids can be used to monitor the status of the graft, for example, to assess the risk of graft rejection. In some examples, the two or more different contributors on two or more genes may include the graft recipient, the fetus, and the graft donor. In some examples, the two or more different contributors on two or more genes may include the graft recipient, a first graft donor, and a second graft donor. For example, the system and method determine an estimated percentage of contributor-derived nucleic acids and / or an estimated percentage of fetal-derived nucleic acids. Abstract
Claims
Attorney Docket No.: 506612003340 CLAIMS 1. A computer-implemented method of determining an amount of contributor- derived cell-free nucleic acids in a mixed sample, obtained from a transplant recipient, comprising cell-free nucleic acids from at least three genetically distinct contributors, the method comprising: receiving, via a computer or an input function, nucleic acid sequence data from a panel of single nucleotide polymorphisms (SNPs) from the cell-free nucleic acids from the at least three genetically distinct contributors; receiving a genomic relationship among the at least three genetically distinct contributors; determining and grouping minor allele frequency (MAF) information from the panel of SNPs; and determining the amount of contributor-derived cell-free nucleic acids based on the genomic relationship and the MAF grouping.
2. The computer-implemented method of claim 1, wherein the transplant recipient is a pregnant woman, and the at least three genetically distinct contributors comprise a maternal genomic contributor, a fetal genomic contributor, and a transplant donor genomic contributor.
3. The computer-implemented method of claim 1, wherein the transplant recipient has received at least two transplants, and the at least three genetically distinct contributors comprise a recipient genomic contributor, a first transplant donor genomic contributor, and a second transplant donor genomic contributor.
4. The computer-implemented method of any of claims 1-3, wherein the amount of contributor-derived cell-free nucleic acids is a percentage of the contributor-derived cell-free nucleic acids in the mixed sample.
5. The computer-implemented method of any of claims 1-4, wherein determining and group MAF information are based on a set of longitudinal samples.
6. The computer-implemented method of claim 5, wherein the set of longitudinal samples have the same genotype. 53sf-5695076Attorney Docket No.: 506612003340 7. The computer-implemented method of any of claims 1-6, wherein the panel of SNPs comprises fewer than 500 SNPs.
8. The computer-implemented method of any of claims 1-7, further comprising: determining a genotype of one or more of: the transplant recipient, a fetus, or a donor based on the MAF information grouping, wherein the transplant recipient is a pregnant woman.
9. The computer-implemented method of any of claims 1-8, wherein determining and grouping MAF information comprises: reordering the panel of SNPs according to mean or median MAF value; determining the MAF information comprising MAF variation summary statistics in the panel of SNPs; and grouping the panel of SNPs according to the MAF variation summary statistics.
10. The computer-implemented method of claim 9, wherein determining and grouping MAF information comprises: determining a separation point in the MAF variation summary statistics by determining a local minimum or maximum in a window.
11. The computer-implemented method of claim 10, wherein the separation point is used to group the SNPs into homozygous and heterozygous genotype groups.
12. The computer-implemented method of any of claims 1-11, wherein determining and grouping MAF information comprises: generating a waterfall plot of the MAF information; grouping the MAF information by segmenting the waterfall plot into groups; and calculating mean MAF values of the groups, wherein the determined amount of contributor-derived cell-free nucleic acids is based on the calculated mean MAF values.
13. The computer-implemented method of any of claims 1-12, wherein determining and grouping MAF information comprises: selecting a first sample comprising a highest mean MAF value among a plurality of samples; 54sf-5695076Attorney Docket No.: 506612003340 selecting a second sample comprising a lowest correlation coefficient associated with the first sample; determining MAF variation summary statistics by subtracting MAF values of the selected first sample and the selected second sample; determining a separation point in the MAF variation summary statistics; and grouping the MAF information based on the separation point.
14. The computer-implemented method of any of claims 1-13, wherein determining and grouping MAF information comprises: selecting an index sample comprising a highest mean MAF value among a plurality of samples; determining an MAF difference between the index sample and each of the plurality of samples; determining MAF variation summary statistics by merging the MAF differences; determining a separation point in the MAF variation summary statistics; and grouping the MAF information based on the separation point.
15. The computer-implemented method of any of claims 1-14, wherein determining and grouping MAF information comprises: selecting a first index sample comprising a highest mean MAF value among a set of high reordered SNPs; selecting a second index sample comprising a highest mean MAF among a set of low reordered SNPs; determining an MAF difference between the first index sample and each of the set of high reordered SNPs; determining an MAF difference between the second index sample and each of the set of low reordered SNPs; determining MAF variation summary statistics by merging the MAF differences; determining a separation point in the MAF variation summary statistics; and grouping the MAF information based on the separation point.
16. The computer-implemented method of any of claims 1-15, further comprising: 55sf-5695076Attorney Docket No.: 506612003340 generating a waterfall plot for the mixed sample, wherein the waterfall plot comprises one or more tiers of stairs having one or more steps, and the SNPs of the one or more steps have the same genotype.
17. The computer-implemented method of any of claims 1-16, wherein the transplant recipient received a transplant comprising one or more of: a kidney transplant, a heart transplant, a lung transplant, a liver transplant, a pancreas transplant, a vascularized composite transplant, an intestinal transplant, a stomach transplant, a testis transplant, a penis transplant, an ovary transplant, a uterus transplant, a thymus transplant, a face transplant, a hand transplant, a leg transplant, a bone transplant, a cornea transplant, skin transplant, a heart valve transplant, a blood vessel transplant, or any combination thereof.
18. The computer-implemented method of any of claims 1-17, wherein the mixed sample is a blood sample.
19. A kit for determining an amount of contributor-derived cell-free nucleic acids in a mixed sample, obtained from a transplant recipient, comprising cell-free nucleic acids from at least three genetically distinct contributors, the kit comprising instructions for: receiving, via a computer or an input function, nucleic acid sequence data from a panel of single nucleotide polymorphisms (SNPs) from the cell-free nucleic acids from the at least three genetically distinct contributors; receiving a genomic relationship among the at least three genetically distinct contributors; determining and grouping minor allele frequency (MAF) information from the panel of SNPs; and determining the amount of contributor-derived cell-free nucleic acids based on the genomic relationship and the MAF grouping.
20. The kit of claim 19, wherein the transplant recipient is a pregnant woman, and the at least three genetically distinct contributors comprise a maternal genomic contributor, a fetal genomic contributor, and a transplant donor genomic contributor. 56sf-5695076Attorney Docket No.: 506612003340 21. The kit of claim 19, wherein the transplant recipient has received at least two transplants, and the at least three genetically distinct contributors comprise a recipient genomic contributor, a first transplant donor genomic contributor, and a second transplant donor genomic contributor.
22. The kit of any of claims 19-21, wherein the amount of contributor-derived cell- free nucleic acids is a percentage of the contributor-derived cell-free nucleic acids in the mixed sample.
23. The kit of any of claims 19-22, wherein determining and group MAF information are based on a set of longitudinal samples.
24. The kit of claim 23, wherein the set of longitudinal samples have the same genotype.
25. The kit of any of claims 19-24, wherein the panel of SNPs comprises fewer than 500 SNPs.
26. The kit of any of claims 19-25, wherein the kit further comprises instructions for: determining a genotype of one or more of: the transplant recipient, a fetus, or a donor based on the MAF information grouping, wherein the transplant recipient is a pregnant woman.
27. The kit of any of claims 19-26, wherein determining and grouping MAF information comprises: reordering the panel of SNPs according to mean or median MAF value; determining the MAF information comprising MAF variation summary statistics in the panel of SNPs; and grouping the panel of SNPs according to the MAF variation summary statistics.
28. The kit of claim 27, wherein determining and grouping MAF information comprises: determining a separation point in the MAF variation summary statistics by determining a local minimum or maximum in a window. 57sf-5695076Attorney Docket No.: 506612003340 29. The kit of claim 28, wherein the separation point is used to group the SNPs into homozygous and heterozygous genotype groups.
30. The kit of any of claims 19-29, wherein determining and grouping MAF information comprises: generating a waterfall plot of the MAF information; grouping the MAF information by segmenting the waterfall plot into groups; and calculating mean MAF values of the groups, wherein the determined amount of contributor-derived cell-free nucleic acids is based on the calculated mean MAF values.
31. The kit of any of claims 19-30, wherein determining and grouping MAF information comprises: selecting a first sample comprising a highest mean MAF value among a plurality of samples; selecting a second sample comprising a lowest correlation coefficient associated with the first sample; determining MAF variation summary statistics by subtracting MAF values of the selected first sample and the selected second sample; determining a separation point in the MAF variation summary statistics; and grouping the MAF information based on the separation point.
32. The kit of any of claims 19-31, wherein determining and grouping MAF information comprises: selecting an index sample comprising a highest mean MAF value among a plurality of samples; determining an MAF difference between the index sample and each of the plurality of samples; determining MAF variation summary statistics by merging the MAF differences; determining a separation point in the MAF variation summary statistics; and grouping the MAF information based on the separation point.
33. The kit of any of claims 19-32, wherein determining and grouping MAF information comprises: 58sf-5695076Attorney Docket No.: 506612003340 selecting a first index sample comprising a highest mean MAF value among a set of high reordered SNPs; selecting a second index sample comprising a highest mean MAF among a set of low reordered SNPs; determining an MAF difference between the first index sample and each of the set of high reordered SNPs; determining an MAF difference between the second index sample and each of the set of low reordered SNPs; determining MAF variation summary statistics by merging the MAF differences; determining a separation point in the MAF variation summary statistics; and grouping the MAF information based on the separation point.
34. The kit of any of claims 19-33, the kit further comprises instructions for: generating a waterfall plot for the mixed sample, wherein the waterfall plot comprises one or more tiers of stairs having one or more steps, and the SNPs of the one or more steps have the same genotype.
35. The kit of any of claims 19-34, wherein the transplant recipient received a transplant comprising one or more of: a kidney transplant, a heart transplant, a lung transplant, a liver transplant, a pancreas transplant, a vascularized composite transplant, an intestinal transplant, a stomach transplant, a testis transplant, a penis transplant, an ovary transplant, a uterus transplant, a thymus transplant, a face transplant, a hand transplant, a leg transplant, a bone transplant, a cornea transplant, skin transplant, a heart valve transplant, a blood vessel transplant, or any combination thereof.
36. The kit of any of claims 19-35, wherein the mixed sample is a blood sample.
37. A system for determining an amount of contributor-derived cell-free nucleic acids in a mixed sample, obtained from a transplant recipient, comprising cell-free nucleic acids from at least three genetically distinct contributors, the system comprising: an interface configured to receive an input; a determination unit configured to: 59sf-5695076Attorney Docket No.: 506612003340 receive, via the interface, nucleic acid sequence data from a panel of single nucleotide polymorphisms (SNPs) from the cell-free nucleic acids from the at least three genetically distinct contributors; receive a genomic relationship among the at least three genetically distinct contributors; determine and group minor allele frequency (MAF) information from the panel of SNPs; and determine the amount of contributor-derived cell-free nucleic acids based on the genomic relationship and the MAF grouping.
38. The system of claim 37, wherein the transplant recipient is a pregnant woman, and the at least three genetically distinct contributors comprise a maternal genomic contributor, a fetal genomic contributor, and a transplant donor genomic contributor.
39. The system of claim 37, wherein the transplant recipient has received at least two transplants, and the at least three genetically distinct contributors comprise a recipient genomic contributor, a first transplant donor genomic contributor, and a second transplant donor genomic contributor.
40. The system of any of claims 37-39, wherein the amount of contributor-derived cell-free nucleic acids is a percentage of the contributor-derived cell-free nucleic acids in the mixed sample.
41. The system of any of claims 37-40, wherein determining and group MAF information are based on a set of longitudinal samples.
42. The system of claim 41, wherein the set of longitudinal samples have the same genotype.
43. The system of any of claims 37-42, wherein the panel of SNPs comprises fewer than 500 SNPs.
44. The system of any of claims 37-43, wherein the determination unit is further configured to: 60sf-5695076Attorney Docket No.: 506612003340 determine a genotype of one or more of: the transplant recipient, a fetus, or a donor based on the MAF information grouping, wherein the transplant recipient is a pregnant woman.
45. The system of any of claims 37-44, wherein the determination unit configured to determine and group MAF information comprises the determination unit configured to: reorder the panel of SNPs according to mean or median MAF value; determine the MAF information comprising MAF variation summary statistics in the panel of SNPs; and group the panel of SNPs according to the MAF variation summary statistics.
46. The system of claim 45, wherein the determination unit configured to determine and group MAF information comprises the determination unit configured to: determine a separation point in the MAF variation summary statistics by determining a local minimum or maximum in a window.
47. The system of claim 46, wherein the separation point is used to group the SNPs into homozygous and heterozygous genotype groups.
48. The system of any of claims 37-47, wherein the determination unit configured to determine and group MAF information comprises the determination unit configured to: generate a waterfall plot of the MAF information; group the MAF information by segmenting the waterfall plot into groups; and calculate mean MAF values of the groups, wherein the determined amount of contributor-derived cell-free nucleic acids is based on the calculated mean MAF values.
49. The system of any of claims 37-48, wherein the determination unit configured to determine and group MAF information comprises the determination unit configured to: select a first sample comprising a highest mean MAF value among a plurality of samples; select a second sample comprising a lowest correlation coefficient associated with the first sample; 61sf-5695076Attorney Docket No.: 506612003340 determine MAF variation summary statistics by subtracting MAF values of the selected first sample and the selected second sample; determine a separation point in the MAF variation summary statistics; and group the MAF information based on the separation point.
50. The system of any of claims 37-49, wherein the determination unit configured to determine and group MAF information comprises the determination unit configured to: select an index sample comprising a highest mean MAF value among a plurality of samples; determine an MAF difference between the index sample and each of the plurality of samples; determine MAF variation summary statistics by merging the MAF differences; determine a separation point in the MAF variation summary statistics; and group the MAF information based on the separation point.
51. The system of any of claims 37-50, wherein the determination unit configured to determine and group MAF information comprises the determination unit configured to: select a first index sample comprising a highest mean MAF value among a set of high reordered SNPs; select a second index sample comprising a highest mean MAF among a set of low reordered SNPs; determine an MAF difference between the first index sample and each of the set of high reordered SNPs; determine an MAF difference between the second index sample and each of the set of low reordered SNPs; determine MAF variation summary statistics by merging the MAF differences; determine a separation point in the MAF variation summary statistics; and group the MAF information based on the separation point.
52. The system of any of claims 37-51, wherein the determination unit is further configured to: 62sf-5695076Attorney Docket No.: 506612003340 generate a waterfall plot for the mixed sample, wherein the waterfall plot comprises one or more tiers of stairs having one or more steps, and the SNPs of the one or more steps have the same genotype.
53. The system of any of claims 37-52, wherein the transplant recipient received a transplant comprising one or more of: a kidney transplant, a heart transplant, a lung transplant, a liver transplant, a pancreas transplant, a vascularized composite transplant, an intestinal transplant, a stomach transplant, a testis transplant, a penis transplant, an ovary transplant, a uterus transplant, a thymus transplant, a face transplant, a hand transplant, a leg transplant, a bone transplant, a cornea transplant, skin transplant, a heart valve transplant, a blood vessel transplant, or any combination thereof.
54. The system of any of claims 37-53, wherein the mixed sample is a blood sample. 63sf-5695076