Biomarkers and methods for predicting preterm birth

Abstract

The disclosure provides biomarker panels, methods and kits for determining the probability for preterm birth in a pregnant female. The present disclosure is based, in part, on the discovery that certain proteins and peptides in biological samples obtained from a pregnant female are differentially expressed in pregnant females that have an increased risk of developing in the future or presently suffering from preterm birth relative to matched controls. The present disclosure is further based, in part, on the unexepected discovery that panels combining one or more of these proteins and peptides can be utilized in methods of determining the probability for preterm birth in a pregnant female with relatively high sensitivity and specificity. These proteins and peptides disclosed herein serve as biomarkers for classifying test samples, predicting a probability of preterm birth, monitoring of progress of preterm birth in a pregnant female, either individually or in a panel of biomarkers.

1 . A panel of isolated biomarkers comprising N of the biomarkers listed in Tables 1 through 63. 
     
     
         2 . The panel of  claim 1 , wherein N is a number selected from the group consisting of 2 to 24. 
     
     
         3 . The panel of  claim 2 , wherein said panel comprises at least two of the isolated biomarkers selected from the group consisting of AFTECCVVASQLR, ELLESYIDGR, ITLPDFTGDLR, the biomarkers set forth in Table 50, and the biomarkers set forth in Table 52. 
     
     
         4 . The panel of  claim 2 , wherein said panel comprises lipopolysaccharide-binding protein (LBP), prothrombin (THRB), complement component C5 (C5 or CO5), plasminogen (PLMN), and complement component C8 gamma chain (C8G or CO8G). 
     
     
         5 . The panel of  claim 2 , wherein said panel comprises at least two isolated biomarkers selected from the group consisting of lipopolysaccharide-binding protein (LBP), prothrombin (THRB), complement component C5 (C5 or CO5), plasminogen (PLMN), and complement component C8 gamma chain (C8G or CO8G). 
     
     
         6 . The panel of  claim 2 , wherein said panel comprises at least two isolated biomarkers selected from the group consisting of lipopolysaccharide-binding protein (LBP), prothrombin (THRB), complement component C5 (C5 or CO5), plasminogen (PLMN), complement component C8 gamma chain (C8G or CO8G), complement component 1, q subcomponent, B chain (C1QB), fibrinogen beta chain (FIBB or FIB), C-reactive protein (CRP), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), chorionic somatomammotropin hormone (CSH), angiotensinogen (ANG or ANGT), the biomarkers set forth in Table 51, and the biomarkers set forth in Table 53. 
     
     
         7 . A method of determining probability for preterm birth in a pregnant female, the method comprising detecting a measurable feature of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63 in a biological sample obtained from said pregnant female, and analyzing said measurable feature to determine the probability for preterm birth in said pregnant female. 
     
     
         8 . The method of  claim 7 , wherein said measurable feature comprises fragments or derivatives of each of said N biomarkers selected from the biomarkers listed in Tables 1 through 63. 
     
     
         9 . The method of  claim 7 , wherein said detecting a measurable feature comprises quantifying an amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63, combinations or portions and/or derivatives thereof in a biological sample obtained from said pregnant female. 
     
     
         10 . The method of  claim 9 , further comprising calculating the probability for preterm birth in said pregnant female based on said quantified amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63. 
     
     
         11 . The method of  claim 7 , further comprising an initial step of providing a biomarker panel comprising N of the biomarkers listed in Tables 1 through 63. 
     
     
         12 . The method of  claim 7 , further comprising an initial step of providing a biological sample from the pregnant female. 
     
     
         13 . The method of  claim 7 , further comprising communicating said probability to a health care provider. 
     
     
         14 . The method of  claim 13 , wherein said communication informs a subsequent treatment decision for said pregnant female. 
     
     
         15 . The method of  claim 7 , wherein N is a number selected from the group consisting of 2 to 24. 
     
     
         16 . The method of  claim 15 , wherein said N biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of AFTECCVVASQLR, ELLESYIDGR, ITLPDFTGDLR, the biomarkers set forth in Table 50, and the biomarkers set forth in Table 52. 
     
     
         17 - 36 . (canceled) 
     
     
         37 . A method of determining probability for preterm birth in a pregnant female, the method comprising: (a) quantifying in a biological sample obtained from said pregnant female an amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63; (b) multiplying said amount by a predetermined coefficient, (c) determining the probability for preterm birth in said pregnant female comprising adding said individual products to obtain a total risk score that corresponds to said probability. 
     
     
         38 . A method of predicting GAB, the method comprising detecting a measurable feature of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63 in a biological sample obtained from a pregnant female, and analyzing said measurable feature to predict GAB. 
     
     
         39 . The method of  claim 38 , wherein said measurable feature comprises fragments or derivatives of each of said N biomarkers selected from the biomarkers listed in Tables 1 through 63. 
     
     
         40 . The method of  claim 38 , wherein said detecting a measurable feature comprises quantifying an amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63, combinations or portions and/or derivatives thereof in a biological sample obtained from said pregnant female. 
     
     
         41 . The method of  claim 40 , further comprising calculating the probability for preterm birth in said pregnant female based on said quantified amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63. 
     
     
         42 . The method of  claim 38 , further comprising an initial step of providing a biomarker panel comprising N of the biomarkers listed in Tables 1 through 63. 
     
     
         43 - 45 . (canceled) 
     
     
         46 . The method of  claim 38 , wherein N is a number selected from the group consisting of 2 to 24. 
     
     
         47 . The method of  claim 46 , wherein said N biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of AFTECCVVASQLR, ELLESYIDGR, ITLPDFTGDLR, the biomarkers set forth in Table 50, and the biomarkers set forth in Table 52. 
     
     
         48 - 65 . (canceled) 
     
     
         66 . A method of prediciting GAB, the method comprising: (a) quantifying in a biological sample obtained from said pregnant female an amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63; (b) multiplying and/or thresholding said amount by a predetermined coefficient, (c) determining the predicted GAB birth in said pregnant female comprising adding said individual products to obtain a total risk score that corresponds to said predicted GAB. 
     
     
         67 . A method of prediciting time to birth in a pregnant female, the method comprising: (a) obtaining a biological sample from said pregnant female; (b) quantifying an amount of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63 in said biological sample; (c) multiplying and/or thresholding said amount by a predetermined coefficient, (d) determining predicted GAB in said pregnant female comprising adding said individual products to obtain a total risk score that corresponds to said predicted GAB; and (e) subtracting the estimated GA at time biological sample was obtained from the predicted GAB to predict time to birth in said pregnant female. 
     
     
         68 . A method of determining probability for term birth in a pregnant female, the method comprising detecting a measurable feature of each of N biomarkers selected from the biomarkers listed in Tables 1 through 63 in a biological sample obtained from said pregnant female, and analyzing said measurable feature to determine the probability for term birth in said pregnant female. 
     
     
         69 . The panel of  claim 2 , wherein said panel comprises at least two of the isolated biomarkers selected from the group consisting of FLNWIK, FGFGGSTDSGPIR, LLELTGPK, VEHSDLSFSK, IEGNLIFDPNNYLPK, ALVLELAK, TQILEWAAER, DVLLLVHNLPQNLPGYFWYK, SEPRPGVLLR, ITQDAQLK, ALDLSLK, WWGGQPLWITATK, and LSETNR. 
     
     
         70 . The panel of  claim 2 , wherein said panel comprises Alpha-1B-glycoprotein (A1BG), Disintegrin and metalloproteinase domain-containing protein 12 (ADA12), Apolipoprotein B-100 (APOB), Beta-2-microglobulin (B2MG), CCAAT/enhancer-binding protein alpha/beta (HP8 Peptide), Corticosteroid-binding globulin (CBG), Complement component C6, Endoglin (EGLN), Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), Coagulation factor VII (FA7), Hyaluronan-binding protein 2 (HABP2), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), Inhibin beta E chain (INHBE). 
     
     
         71 . The panel of  claim 2 , wherein said panel comprises at least two isolated biomarkers selected from the group consisting Alpha-1B-glycoprotein (A1BG), Disintegrin and metalloproteinase domain-containing protein 12 (ADA12), Apolipoprotein B-100 (APOB), Beta-2-microglobulin (B2MG), CCAAT/enhancer-binding protein alpha/beta (HP8 Peptide), Corticosteroid-binding globulin (CBG), Complement component C6, Endoglin (EGLN), Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), Coagulation factor VII (FA7), Hyaluronan-binding protein 2 (HABP2), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), Inhibin beta E chain (INHBE). 
     
     
         72 . The method of  claim 38 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of FLNWIK, FGFGGSTDSGPIR, LLELTGPK, VEHSDLSFSK, IEGNLIFDPNNYLPK, ALVLELAK, TQILEWAAER, DVLLLVHNLPQNLPGYFWYK, SEPRPGVLLR, ITQDAQLK, ALDLSLK, WWGGQPLWITATK, and LSETNR. 
     
     
         73 . The method of  claim 66 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of FLNWIK, FGFGGSTDSGPIR, LLELTGPK, VEHSDLSFSK, IEGNLIFDPNNYLPK, ALVLELAK, TQILEWAAER, DVLLLVHNLPQNLPGYFWYK, SEPRPGVLLR, ITQDAQLK, ALDLSLK, WWGGQPLWITATK, and LSETNR. 
     
     
         74 . The method of  claim 67 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of FLNWIK, FGFGGSTDSGPIR, LLELTGPK, VEHSDLSFSK, IEGNLIFDPNNYLPK, ALVLELAK, TQILEWAAER, DVLLLVHNLPQNLPGYFWYK, SEPRPGVLLR, ITQDAQLK, ALDLSLK, WWGGQPLWITATK, and LSETNR. 
     
     
         75 . The method of  claim 68 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of FLNWIK, FGFGGSTDSGPIR, LLELTGPK, VEHSDLSFSK, IEGNLIFDPNNYLPK, ALVLELAK, TQILEWAAER, DVLLLVHNLPQNLPGYFWYK, SEPRPGVLLR, ITQDAQLK, ALDLSLK, WWGGQPLWITATK, and LSETNR. 
     
     
         76 . The method of  claim 38 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of Alpha-1 B-glycoprotein (A1BG), Disintegrin and metalloproteinase domain-containing protein 12 (ADA12), Apolipoprotein B-100 (APOB), Beta-2-microglobulin (B2MG), CCAAT/enhancer-binding protein alpha/beta (HP8 Peptide), Corticosteroid-binding globulin (CBG), Complement component C6, Endoglin (EGLN), Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), Coagulation factor VII (FA7), Hyaluronan-binding protein 2 (HABP2), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), Inhibin beta E chain (INHBE). 
     
     
         77 . The method of  claim 66 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of Alpha-1 B-glycoprotein (A1BG), Disintegrin and metalloproteinase domain-containing protein 12 (ADA12), Apolipoprotein B-100 (APOB), Beta-2-microglobulin (B2MG), CCAAT/enhancer-binding protein alpha/beta (HP8 Peptide), Corticosteroid-binding globulin (CBG), Complement component C6, Endoglin (EGLN), Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), Coagulation factor VII (FA7), Hyaluronan-binding protein 2 (HABP2), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), Inhibin beta E chain (INHBE). 
     
     
         78 . The method of  claim 67 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of Alpha-1 B-glycoprotein (A1BG), Disintegrin and metalloproteinase domain-containing protein 12 (ADA12), Apolipoprotein B-100 (APOB), Beta-2-microglobulin (B2MG), CCAAT/enhancer-binding protein alpha/beta (HP8 Peptide), Corticosteroid-binding globulin (CBG), Complement component C6, Endoglin (EGLN), Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), Coagulation factor VII (FA7), Hyaluronan-binding protein 2 (HABP2), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), Inhibin beta E chain (INHBE). 
     
     
         79 . The method of  claim 68 , wherein said biomarkers comprise at least two of the isolated biomarkers selected from the group consisting of Alpha-1 B-glycoprotein (A1BG), Disintegrin and metalloproteinase domain-containing protein 12 (ADA12), Apolipoprotein B-100 (APOB), Beta-2-microglobulin (B2MG), CCAAT/enhancer-binding protein alpha/beta (HP8 Peptide), Corticosteroid-binding globulin (CBG), Complement component C6, Endoglin (EGLN), Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), Coagulation factor VII (FA7), Hyaluronan-binding protein 2 (HABP2), Pregnancy-specific beta-1-glycoprotein 9 (PSG9), Inhibin beta E chain (INHBE).