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US 10,870,888 B2Granted
Methods and systems for analysis of organ transplantation
AssigneesThe Scripps Research Institute, Northwestern University
InventorsDaniel Salomon, Sunil M. Kurian, Steven Head, Michael M. Abecassis, John J. Friedewald, Josh Levitsky
Life of this patent
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Abstract
Disclosed herein are methods of detecting, predicting or monitoring a status or outcome of a transplant in a transplant recipient.
Claims31
A method of detecting gene expression products and treating acute rejection in a transplant recipient on an immunosuppressive drug, the method comprising:
- (a) obtaining a blood sample, wherein the blood sample comprises mRNA from the transplant recipient on an immunosuppressive drug or DNA complements of mRNA from the transplant recipient on an immunosuppressive drug;
- (b) performing a microarray assay or sequencing assay to determine an expression level of the mRNA from the transplant recipient on an immunosuppressive drug or DNA complements of mRNA from the transplant recipient on an immunosuppressive drug;
- (c) detecting or predicting acute rejection in the transplant recipient by applying a trained algorithm to the expression level determined in step (b), wherein the trained algorithm comprises one or more classifiers, wherein the trained algorithm is trained on 25 or more genes selected from the group consisting of SMARCB1, STP6AP2, PLEKHA3, TP53, PRKAG2, ND2, YWHAE, SSR1, CCDC91, PRKAG2, ADPGK, CHFR, PRNP, CDYL, SPTLC1, CHMP1B, KBTBD2, MST4, CDC42EP3, UBXN4, PGGT1B, CCR2, ZNF426, SP1, MED18, FLI1, LUC7L2, CD46, CASKIN1, UGP2, ARNTL, PLEKHF2, ZNF117, ITGB1, MAP3K1, FBXW7, SRGAP2B, ZNF136, ARPC5, FBXL18, TMED2, YWHAZ, SNAP23, TMEM30A, CD46, INSIG1, SRSF2, API5, FLI1, SLC35E1, PAPOLA, MLLT10, SLC35B4, ARL2BP, CNOT8, SYPL1, BRWD3, RBBP4, GLCCI1, MBP, RAB8B, YTHDF3, TOR1AIP1, ATF1, TMEM230, LRCH3, ARID2, CNOT8, ZBTB20, PSMD10, RHOP, ATF71P, LOC100131541, STYX, CN1H4, EMC1, MACF1, NOP14-AS1, HHEX, DHX36, DAPP1, WTAP, PSEN1, MAP3K7, PPP2R5E, FAM108B1, TAB2, FAR1, METTL21A, FYTTD1, TMED2, TROVE2, LNPEP, CAB39, RC3H2, SLBP, SNAP23, VWA9, MGAT2, OCIAD1, SH2D1B, PEX7, CD4, BZW1, RNF125, GNL3L, TRMT10B, RHEB, TMF1, STAG3L1, WSB1, PDE4B, ARID2, ATXN3, CUL4B, PRMT2, CTSS, ANAPC2, GLUD1, SGPP1, FAM178A, 2-Sep, KCTD5, ZEB1, RAC1, UVSSA, RBM4, ALKBH7, 214405_PM_at_EST1, SIVA1, 214482_PM_at_EST2, CHD2, POLR2C, 1556865_PM_at_EST3, GTF2H4, RNF25, DICER1, C9orf86, C5orf24, KIDINS220, ADPGK, HNRNPA0, 236237_PM_at_EST4, BAX, MBNL1, RAB5A, POLR2G, CELF2, 1561909_PM_at_EST5, FNBP1, FOXO3 /// FOXO3B, 233303_PM_at_EST6, 244219_PM_at_EST7, R3HCC1, DLST, CALM3, U2AF1, ANTXR2, LILRA4, TLE4, SMARCC1, BET1L, VAMP2, MRPS18A, KLF7, 242726_PM_at_EST8, USP34, APPL2, 240991_PM_at_EST9, NCR3, TXN1P, SDHAF1, HECTD1, C6orf62, 243751_PM_at_EST10, ATAD2B, MLL3, ATF6, Clorf128, SERPINF1, PAFAH1B1, C2ORF7, FOXO3 /// FOXO3B, CHMP4A, ANXA11, TAF10, DLEU2, 15622_PM_at_EST11, SEPT9, RBM5, MGEA5, TRAF4, LOC100132707, OTUD4, KLHL12, MED1, 216112_PM_at_EST12, ACSL4, ATXN7L3b, DCTN3, MGEA4, MS4A6A, CCDC69, H2AFY, TMEM165, INO80D, PSEN1, C15orf17, RBM27, GZMM, ATP6, ZDHHC1, TLE4, SDHC, HNRNPUL1, SF3A2, 236545_PM_at_EST13, CDH23, LOC100506866, C4orf48, EMD, NEK1, HNRNPM, 241240_PM_at_EST15, LIMD2, THOC2, 243046_PM_at_EST16, BAT2L2, ZCCHC6, 228723_PM_at_EST17, 242695_PM_at_EST18, PLEC, U1MC1, LRRFIP1, 1556055_PM_at_EST19, AFFX-, M27830_5_at_EST20, GRB10, CD84, KLHDC3, BAX, NRD1, RASA2, 1559589_PM_a_at_EST21, MTPAP, ZFP36L2, AGPAT1, KIDINS220, ISOC2, KLF7, MED27, TLR4, ABHD14B, 244349_PM_at_EST22, 244418_PM_at_EST23, MLXIP, PPID, MRPL43, ND3 /// SH3KBP1, TNRC6B, KLHL28, SLC25A37, NELF, FARS2, ZCCHC6, TRIM25, TAF15, LTB, 221995_PM_s_at_EST24, IFNGR1, 228826_PM_at_EST25, C7orf16, NEDD9, NDUFA7, ZC3H11A, DNAJA4, ERICH1, RALB, MPZL1, EZR, RBKS, TMOD1 /// TSTD2, LOC729683, PTK2B, APBB11P, UBXN4, SETD5, 243032_PM_at_EST26, 216380_PM_x_at_EST27, TRAPPC4, CKB, CANX, 1558624_PM_at_EST28, SIVA1, 240652_PM_at_EST29, HOXA1, C11orf49, SLC11A1, C9orf86, IVNS1ABP, PDXP /// SH3BP1, CHTF8, FKBP5, FGFR1OP2, SECISBP2L, ARF1, B4GALT1, PHF19, C16orf5, C11orf59, PIP4K2A, GCLC, EMILIN2, NGLY1, ANKHD1 /// ANKHD1-EIF4EBP3, DLEU2, PBLS, RALGAPA2, 230733_PM_at_EST30, 1557804_PM_at_EST31, PKN2, and GGNBP2, wherein the trained algorithm is capable of distinguishing between acute rejection and acute dysfunction with no rejection, and wherein the trained algorithm has a negative predictive value of greater than 70%;
- and
- (d) administering a higher dosage of the immunosuppressive drug or administering a new immunosuppressive drug in order to treat or prevent the acute rejection detected or predicted in the transplant recipient in step (c).
2 more elements
A method of detecting gene expression products and treating acute rejection in a transplant recipient on an immunosuppressive drug, the method comprising:
- (a) obtaining a blood sample, wherein the blood sample comprises mRNA from the transplant recipient or DNA complements of mRNA from the transplant recipient;
- (b) performing a microarray assay or sequencing assay to determine an expression level of mRNA from the transplant recipient or DNA complements of mRNA from the transplant recipient;
- and
- (c) detecting or predicting acute rejection in the transplant recipient by applying a trained algorithm to the expression level determined in step (b), wherein the trained algorithm is trained on 25 or more genes selected from the group consisting of SMARCB1, STP6AP2, PLEKHA3, TP53, PRKAG2, ND2, YWHAE, SSR1, CCDC91, PRKAG2, ADPGK, CHFR, PRNP, CDYL, SPTLC1, CHMP1B, KBTBD2, MST4, CDC42EP3, UBXN4, PGGT1B, CCR2, ZNF426, SP1, MED18, FLI1, LUC7L2, CD46, CASKIN1, UGP2, ARNTL, PLEKHF2, ZNF117, ITGB1, MAP3K1, FBXW7, SRGAP2B, ZNF136, ARPC5, FBXL18, TMED2, YWHAZ, SNAP23, TMEM30A, CD46, INSIG1, SRSF2, API5, FLI1, SLC35E1, PAPOLA, MLLT10, SLC35B4, ARL2BP, CNOT8, SYPL1, BRWD3, RBBP4, GLCCI1, MBP, RAB8B, YTHDF3, TOR1AIP1, ATF1, TMEM230, LRCH3, ARID2, CNOT8, ZBTB20, PSMD10, RHOP, ATF71P, LOC100131541, STYX, CN1H4, EMC1, MACF1, NOP14-AS1, HHEX, DHX36, DAPP1, WTAP, PSEN1, MAP3K7, PPP2R5E, FAM108B1, TAB2, FAR1, METTL21A, FYTTD1, TMED2, TROVE2, LNPEP, CAB39, RC3H2, SLBP, SNAP23, VWA9, MGAT2, OCIAD1, SH2D1B, PEX7, CD4, BZW1, RNF125, GNL3L, TRMT10B, RHEB, TMF1, STAG3L1, WSB1, PDE4B, ARID2, ATXN3, CUL4B, PRMT2, CTSS, ANAPC2, GLUD1, SGPP1, FAM178A, 2-Sep, KCTD5, ZEB1, RAC1, UVSSA, RBM4, ALKBH7, 214405_PM_at_EST1, SIVA1, 214482_PM_at_EST2, CHD2, POLR2C, 1556865_PM_at_EST3, GTF2H4, RNF25, DICER1, C9orf86, C5orf24, KIDINS220, ADPGK, HNRNPA0, 236237_PM_at_EST4, BAX, MBNL1, RAB5A, POLR2G, CELF2, 1561909_PM_at_EST5, FNBP1, FOXO3 /// FOXO3B, 233303_PM_at_EST6, 244219_PM_at_EST7, R3HCC1, DLST, CALM3, U2AF1, ANTXR2, LILRA4, TLE4, SMARCC1, BET1L, VAMP2, MRPS18A, KLF7, 242726_PM_at_EST8, USP34, APPL2, 240991_PM_at_EST9, NCR3, TXN1P, SDHAF1, HECTD1, C6orf62, 243751_PM_at_EST10, ATAD2B, MLL3, ATF6, Clorf128, SERPINF1, PAFAH1B1, C2ORF7, FOXO3 /// FOXO3B, CHMP4A, ANXA11, TAF10, DLEU2, 15622_PM_at_EST11, SEPT9, RBM5, MGEA5, TRAF4, LOC100132707, OTUD4, KLHL12, MED1, 216112_PM_at_EST12, ACSL4, ATXN7L3b, DCTN3, MGEA4, MS4A6A, CCDC69, H2AFY, TMEM165, INO80D, PSEN1, C15orf17, RBM27, GZMM, ATP6, ZDHHC1, TLE4, SDHC, HNRNPUL1, SF3A2, 236545_PM_at_EST13, CDH23, LOC100506866, C4orf48, EMD, NEK1, HNRNPM, 241240_PM_at_EST15, LIMD2, THOC2, 243046_PM_at_EST16, BAT2L2, ZCCHC6, 228723_PM_at_EST17, 242695_PM_at_EST18, PLEC, U1MC1, LRRFIP1, 1556055_PM_at_EST19, AFFX-, M27830_5_at_EST20, GRB10, CD84, KLHDC3, BAX, NRD1, RASA2, 1559589_PM_a_at_EST21, MTPAP, ZFP36L2, AGPAT1, KIDINS220, ISOC2, KLF7, MED27, TLR4, ABHD14B, 244349_PM_at_EST22, 244418_PM_at_EST23, MLXIP, PPID, MRPL43, ND3 /// SH3KBP1, TNRC6B, KLHL28, SLC25A37, NELF, FARS2, ZCCHC6, TRIM25, TAF15, LTB, 221995_PM_s_at_EST24, IFNGR1, 228826_PM_at_EST25, C7orf16, NEDD9, NDUFA7, ZC3H11A, DNAJA4, ERICH1, RALB, MPZL1, EZR, RBKS, TMOD1 /// TSTD2, LOC729683, PTK2B, APBB11P, UBXN4, SETD5, 243032_PM_at_EST26, 216380_PM_x_at_EST27, TRAPPC4, CKB, CANX, 1558624_PM_at_EST28, SIVA1, 240652_PM_at_EST29, HOXA1, C11orf49, SLC11A1, C9orf86, IVNS1ABP, PDXP /// SH3BP1, CHTF8, FKBP5, FGFR1OP2, SECISBP2L, ARF1, B4GALT1, PHF19, C16orf5, C11orf59, PIP4K2A, GCLC, EMILIN2, NGLY1, ANKHD1 /// ANKHD1-EIF4EBP3, DLEU2, PBLS, RALGAPA2, 230733_PM_at_EST30, 1557804_PM_at_EST31, PKN2, and GGNBP2, wherein the trained algorithm is a three-way classifier capable of distinguishing between at least three conditions, and wherein one of the at least three conditions is acute rejection, wherein one of the at least three conditions is acute dysfunction with no rejection, and wherein the trained algorithm has a negative predictive value of greater than 70%;
- and
- (d) administering a higher dosage of the immunosuppressive drug or administering a new immunosuppressive drug in order to treat the acute rejection detected or predicted in the transplant recipient in step (c).
3 more elements
Dependencies are inferred from the claim text.