Pregnancy clock proteins for predicting due date and time to birth

Abstract

The present invention provides compositions and methods for due date and time to birth prediction for a pregnancy with significantly higher accuracy than current clinical methods. The compositions and methods for due date and time to birth prediction for a pregnancy can also identify those pregnancies that will deliver earlier than the due date derived from LMP and/or US dating.

1 . A panel comprising a pair of isolated biomarkers, wherein said pair of isolated biomarkers comprises Disintegrin and metalloproteinase domain-containing protein 12 (ADA12) and an isolated biomarker selected from the group consisting of Mast/stem cell growth factor receptor Kit (KIT), Leucine-rich alpha-2-glycoprotein (A2GL), Alpha-2-HS-glycoprotein (FETUA), Insulin-like growth factor I (IGF1), Chorionic somatomammotropin hormone 1 (CSH), Pregnancy-specific beta-1-glycoprotein 1 (PSG1), Pregnancy-specific beta-1-glycoprotein 11 (PSG11), Pregnancy-specific beta-1-glycoprotein 2 (PSG2), Pregnancy-specific beta-1-glycoprotein 3 (PSG3), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), and Growth hormone variant (SOM2), wherein said pair of isolated biomarkers exhibits a change in reversal value between pregnant females that deliver before 270 days relative to pregnant females that deliver on or after 280 days. 
     
     
         2 . (canceled) 
     
     
         3 . A method of determining the estimated due date (EDD) or time to birth (TTB) for a pregnant female, the method comprising:
 (a) detecting the presence or amount of a pair of isolated biomarkers in a biological sample obtained from a pregnant female; and   (b) measuring in said biological sample a reversal value for said pair of isolated biomarkers,   wherein said reversal value predicts the EDD or TTB for said pregnant female in a predictive model,   wherein detecting comprises subjecting said biological sample to: (i) a proteomics work-flow comprised of mass spectrometry (MS) quantification: or (ii) an assay that utilizes a capture agent that binds to at least one biomarker of said pair of isolated biomarkers,   wherein said biological sample is selected from the group consisting of whole blood, plasma, and serum, and   wherein said pair of isolated biomarkers comprises Disintegrin and metalloproteinase domain-containing protein 12 (ADA12) and an isolated biomarker selected from the group consisting of Mast/stem cell growth factor receptor Kit (KIT), Leucine-rich alpha-2-glycoprotein (A2GL), Alpha-2-HS-glycoprotein (FETUA), Insulin-like growth factor I (IGF1), Chorionic somatomammotropin hormone 1 (CSH), Pregnancy-specific beta-1-glycoprotein 1 (PSG1), Pregnancy-specific beta-1-glycoprotein 11 (PSG11), Pregnancy-specific beta-1-glycoprotein 2 (PSG2), Pregnancy-specific beta-1-glycoprotein 3 (PSG3), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), and Growth hormone variant (SOM2).   
     
     
         4 . The method of  claim 3 , wherein the biological sample is obtained at a gestational age at blood draw (GABD) from 18 0/7 weeks through 22 6/7 weeks. 
     
     
         5 . The method of  claim 3 , wherein the biological sample is obtained at a gestational age at blood draw (GABD) from 23 0/7 weeks through 28 6/7 weeks. 
     
     
         6 . The method of  claim 3 , wherein said pregnant female is nulliparous. 
     
     
         7 . The method of  claim 3 , further comprising calculation of Inverse Parity as 1/(Parity−0.5). 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 3 , wherein the biological sample is serum. 
     
     
         12 . The method of  claim 3 , wherein said detecting comprises mass spectrometry (MS). 
     
     
         13 . The method of  claim 3 , wherein said detecting comprises said assay that utilizes a capture agent that binds to at least one biomarker of said pair of isolated biomarkers. 
     
     
         14 . The method of  claim 13 , wherein said capture agent is selected from the group consisting of and antibody, antibody fragment, nucleic acid-based protein binding reagent, small molecule or variant thereof. 
     
     
         15 . The method of  claim 13 , wherein said assay is selected from the group consisting of enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), and radioimmunoassay (RIA). 
     
     
         16 . The method of  claim 3 , further comprising determining gestational age at birth (GAB). 
     
     
         17 . A method of detecting a reversal value for a pair of isolated biomarkers in a biological sample obtained from a pregnant female, the method comprising:
 (a) detecting the presence or amount of said pair of isolated biomarkers in said biological sample obtained from said pregnant female; and   (b) measuring in said biological sample a reversal value for said pair of isolated biomarkers,   wherein detecting comprises subjecting said biological sample to: (i) a proteomics work-flow comprised of mass spectrometry (MS) quantification: or (ii) an assay that utilizes a capture agent that binds to at least one biomarker of said pair of isolated biomarkers,   wherein said biological sample is selected from the group consisting of whole blood, plasma, and serum, and   wherein said pair of isolated biomarkers comprises Disintegrin and metalloproteinase domain-containing protein 12 (ADA12) and an isolated biomarker selected from the group consisting Mast/stem cell growth factor receptor Kit (KIT), Leucine-rich alpha-2-glycoprotein (A2GL), Alpha-2-HS-glycoprotein (FETUA), Insulin-like growth factor I (IGF1), Chorionic somatomammotropin hormone 1 (CSH), Pregnancy-specific beta-1-glycoprotein 1 (PSG1), Pregnancy-specific beta-1-glycoprotein 11 (PSG11), Pregnancy-specific beta-1-glycoprotein 2 (PSG2), Pregnancy-specific beta-1-glycoprotein 3 (PSG3), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), and Growth hormone variant (SOM2).   
     
     
         18 . The panel of  claim 1 , wherein said pair of isolated biomarkers comprises ADA12 and an isolated biomarker selected from the group consisting of CSH, PSG1, PSG11, PSG2, PSG3, PSG9, and SOM2. 
     
     
         19 . The panel of  claim 1 , wherein said pair of isolated biomarkers comprises ADA12 and KIT. 
     
     
         20 . The panel of  claim 1 , wherein said pair of isolated biomarkers comprises ADA12 and an isolated biomarker selected from the group consisting of A2GL, FETUA, and IGF1. 
     
     
         21 . The method of  claim 3 , wherein said pair of isolated biomarkers comprises ADA12 and an isolated biomarker selected from the group consisting of CSH, PSG1, PSG11, PSG2, PSG3, PSG9, and SOM2. 
     
     
         22 . The method of  claim 3 , wherein said pair of isolated biomarkers comprises ADA12 and KIT. 
     
     
         23 . The method of  claim 3 , wherein said pair of isolated biomarkers comprises ADA12 and an isolated biomarker selected from the group consisting of A2GL, FETUA, and IGF1. 
     
     
         24 . The method of  claim 17 , wherein said pair of isolated biomarkers comprises ADA12 and an isolated biomarker selected from the group consisting of CSH, PSG1, PSG11, PSG2, PSG3, PSG9, and SOM2. 
     
     
         25 . The method of  claim 17 , wherein said pair of isolated biomarkers comprises ADA12 and KIT. 
     
     
         26 . The method of  claim 17 , wherein said pair of isolated biomarkers comprises ADA12 and an isolated biomarker selected from the group consisting of A2GL, FETUA, and IGF1. 
     
     
         27 . The panel of  claim 1 , wherein:
 (a) the pair of isolated biomarkers comprising ADA12 comprises a peptide fragment comprising the amino acid sequence FGFGGSTDSGPIR (SEQ ID NO: 84);   (b) the pair of isolated biomarkers comprising KIT comprises a peptide fragment comprising the amino acid sequence LCLHCSVDQEGK (SEQ ID NO: 161);   (c) the pair of isolated biomarkers comprising KIT comprises a peptide fragment comprising the amino acid sequence YVSELHLTR (SEQ ID NO: 162);   (d) the pair of isolated biomarkers comprising A2GL comprises a peptide fragment comprising the amino acid sequence DLLLPQPDLR (SEQ ID NO: 29);   (e) the pair of isolated biomarkers comprising FETUA comprises a peptide fragment comprising the amino acid sequence FSVVYAK (SEQ ID NO: 50);   (f) the pair of isolated biomarkers comprising FETUA comprises a peptide fragment comprising the amino acid sequence HTLNQIDEVK (SEQ ID NO: 51);   (g) the pair of isolated biomarkers comprising IGF1 comprises a peptide fragment comprising the amino acid sequence GFYFNKPTGYGSSSR (SEQ ID NO: 115);   (h) the pair of isolated biomarkers comprising CSH comprises a peptide fragment comprising the amino acid sequence AHQLAIDTYQEFEETYIPK (SEQ ID NO: 33);   (i) the pair of isolated biomarkers comprising CSH comprises a peptide fragment comprising the amino acid sequence ISLLLIESWLEPVR (SEQ ID NO: 43);   (j) the pair of isolated biomarkers comprising PSG1 comprises a peptide fragment comprising the amino acid sequence FQLPGQK (SEQ ID NO: 80);   (k) the pair of isolated biomarkers comprising PSG11 comprises a peptide fragment comprising the amino acid sequence LFIPQITPK (SEQ ID NO: 57);   (l) the pair of isolated biomarkers comprising PSG2 comprises a peptide fragment comprising the amino acid sequence IHPSYTNYR (SEQ ID NO: 52);   (m) the pair of isolated biomarkers comprising PSG3 comprises a peptide fragment comprising the amino acid sequence VSAPSGTGHLPGLNPL (SEQ ID NO: 76);   (n) the pair of isolated biomarkers comprising PSG9 comprises a peptide fragment comprising the amino acid sequence DVLLLVHNLPQNLPGYFWYK (SEQ ID NO: 59);   (o) the pair of isolated biomarkers comprising PSG9 comprises a peptide fragment comprising the amino acid sequence LFIPQITR (SEQ ID NO: 58);   (p) the pair of isolated biomarkers comprising SOM2 comprises a peptide fragment comprising the amino acid sequence NYGLLYCFR (SEQ ID NO: 108); or   (q) the pair of isolated biomarkers comprising SOM2 comprises a peptide fragment comprising the amino acid sequence SVEGSCGF (SEQ ID NO: 109).   
     
     
         28 . The method of  claim 3 , wherein:
 (a) the pair of isolated biomarkers comprising ADA12 comprises a peptide fragment comprising the amino acid sequence FGFGGSTDSGPIR (SEQ ID NO: 84);   (b) the pair of isolated biomarkers comprising KIT comprises a peptide fragment comprising the amino acid sequence LCLHCSVDQEGK (SEQ ID NO: 161);   (c) the pair of isolated biomarkers comprising KIT comprises a peptide fragment comprising the amino acid sequence YVSELHLTR (SEQ ID NO: 162);   (d) the pair of isolated biomarkers comprising A2GL comprises a peptide fragment comprising the amino acid sequence DLLLPQPDLR (SEQ ID NO: 29);   (e) the pair of isolated biomarkers comprising FETUA comprises a peptide fragment comprising the amino acid sequence FSVVYAK (SEQ ID NO: 50);   (f) the pair of isolated biomarkers comprising FETUA comprises a peptide fragment comprising the amino acid sequence HTLNQIDEVK (SEQ ID NO: 51);   (g) the pair of isolated biomarkers comprising IGF1 comprises a peptide fragment comprising the amino acid sequence GFYFNKPTGYGSSSR (SEQ ID NO: 115);   (h) the pair of isolated biomarkers comprising CSH comprises a peptide fragment comprising the amino acid sequence AHQLAIDTYQEFEETYIPK (SEQ ID NO: 33);   (i) the pair of isolated biomarkers comprising CSH comprises a peptide fragment comprising the amino acid sequence ISLLLIESWLEPVR (SEQ ID NO: 43);   (j) the pair of isolated biomarkers comprising PSG1 comprises a peptide fragment comprising the amino acid sequence FQLPGQK (SEQ ID NO: 80);   (k) the pair of isolated biomarkers comprising PSG11 comprises a peptide fragment comprising the amino acid sequence LFIPQITPK (SEQ ID NO: 57);   (l) the pair of isolated biomarkers comprising PSG2 comprises a peptide fragment comprising the amino acid sequence IHPSYTNYR (SEQ ID NO: 52);   (m) the pair of isolated biomarkers comprising PSG3 comprises a peptide fragment comprising the amino acid sequence VSAPSGTGHLPGLNPL (SEQ ID NO: 76);   (n) the pair of isolated biomarkers comprising PSG9 comprises a peptide fragment comprising the amino acid sequence DVLLLVHNLPQNLPGYFWYK (SEQ ID NO: 59);   (o) the pair of isolated biomarkers comprising PSG9 comprises a peptide fragment comprising the amino acid sequence LFIPQITR (SEQ ID NO: 58);   (p) the pair of isolated biomarkers comprising SOM2 comprises a peptide fragment comprising the amino acid sequence NYGLLYCFR (SEQ ID NO: 108); or   (q) the pair of isolated biomarkers comprising SOM2 comprises a peptide fragment comprising the amino acid sequence SVEGSCGF (SEQ ID NO: 109).   
     
     
         29 . The method of  claim 17 , wherein:
 (a) the pair of isolated biomarkers comprising ADA12 comprises a peptide fragment comprising the amino acid sequence FGFGGSTDSGPIR (SEQ ID NO: 84);   (b) the pair of isolated biomarkers comprising KIT comprises a peptide fragment comprising the amino acid sequence LCLHCSVDQEGK (SEQ ID NO: 161);   (c) the pair of isolated biomarkers comprising KIT comprises a peptide fragment comprising the amino acid sequence YVSELHLTR (SEQ ID NO: 162);   (d) the pair of isolated biomarkers comprising A2GL comprises a peptide fragment comprising the amino acid sequence DLLLPQPDLR (SEQ ID NO: 29);   (e) the pair of isolated biomarkers comprising FETUA comprises a peptide fragment comprising the amino acid sequence FSVVYAK (SEQ ID NO: 50);   (f) the pair of isolated biomarkers comprising FETUA comprises a peptide fragment comprising the amino acid sequence HTLNQIDEVK (SEQ ID NO: 51);   (g) the pair of isolated biomarkers comprising IGF1 comprises a peptide fragment comprising the amino acid sequence GFYFNKPTGYGSSSR (SEQ ID NO: 115);   (h) the pair of isolated biomarkers comprising CSH comprises a peptide fragment comprising the amino acid sequence AHQLAIDTYQEFEETYIPK (SEQ ID NO: 33);   (i) the pair of isolated biomarkers comprising CSH comprises a peptide fragment comprising the amino acid sequence ISLLLIESWLEPVR (SEQ ID NO: 43);   (j) the pair of isolated biomarkers comprising PSG1 comprises a peptide fragment comprising the amino acid sequence FQLPGQK (SEQ ID NO: 80);   (k) the pair of isolated biomarkers comprising PSG11 comprises a peptide fragment comprising the amino acid sequence LFIPQITPK (SEQ ID NO: 57);   (l) the pair of isolated biomarkers comprising PSG2 comprises a peptide fragment comprising the amino acid sequence IHPSYTNYR (SEQ ID NO: 52);   (m) the pair of isolated biomarkers comprising PSG3 comprises a peptide fragment comprising the amino acid sequence VSAPSGTGHLPGLNPL (SEQ ID NO: 76);   (n) the pair of isolated biomarkers comprising PSG9 comprises a peptide fragment comprising the amino acid sequence DVLLLVHNLPQNLPGYFWYK (SEQ ID NO: 59);   (o) the pair of isolated biomarkers comprising PSG9 comprises a peptide fragment comprising the amino acid sequence LFIPQITR (SEQ ID NO: 58);   (p) the pair of isolated biomarkers comprising SOM2 comprises a peptide fragment comprising the amino acid sequence NYGLLYCFR (SEQ ID NO: 108); or   (q) the pair of isolated biomarkers comprising SOM2 comprises a peptide fragment comprising the amino acid sequence SVEGSCGF (SEQ ID NO: 109).   
     
     
         30 . The method of  claim 12 , wherein said MS is selected from the group consisting of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS; MALDI-TOF post-source-decay (PSD); MALDI-TOF/TOF; surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF) MS; electrospray ionization mass spectrometry (ESI-MS); ESI-MS/MS; ESI-MS/(MS)n (n is an integer greater than zero); ESI 3D or linear (2D) ion trap MS; ESI triple quadrupole MS; ESI quadrupole orthogonal TOF (Q-TOF); ESI Fourier transform MS systems; desorption/ionization on silicon (DIOS); secondary ion mass spectrometry (SIMS); atmospheric pressure chemical ionization mass spectrometry (APCI-MS); APCI-MS; APCI-(MS)n; ion mobility spectrometry (IMS); inductively coupled plasma mass spectrometry (ICP-MS) atmospheric pressure photoionization mass spectrometry (APPI-MS), APPI-MS/MS; and APPI-(MS)n. 
     
     
         31 . The method of  claim 12 , wherein said MS comprises affinity-capture MS (AC-MS), co-immunoprecipitation-mass spectrometry (co-TP MS), liquid chromatography-mass spectrometry (LC-MS), multiple reaction monitoring (MR) or selected reaction monitoring (SRM).