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AssigneeSomaLogic Operating Co., Inc.
InventorsKelsey M. Loupy, Rachel M. Ostroff, Lori K. Bogren, Laura Mae Sampson, Amy Zhang, Natasha Kureshi, Hannah Biegel, Clare Paterson, Yolanda Hagar, Leigh Alexander
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The present disclosure includes biomarkers, methods, devices, reagents, systems, and kits for the evaluation of risk of dementia in a middle-aged individual within a specified timeframe, for example 5, 10, 15 and/or 20 years. In one aspect, the disclosure provides biomarkers that can be used alone or in various combinations to evaluate risk of dementia within 5, 10, 15 and/or 20 years. In another aspect, methods are provided for evaluating risk of dementia within 5, 10, 15 and/or 20 years in a middle-aged individual, where the methods include detecting, in a biological sample from an individual, at least one biomarker value corresponding to at least one biomarker selected from the group of biomarkers provided in Table 6.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of CILP2 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from PTN, PH, Notch1, NADK, CDON, MP2k2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of detecting levels of N biomarker proteins in a sample, comprising obtaining the sample from the subject, and detecting the level of each of the N biomarker proteins in the sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of PTN biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of PH biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of Notch1 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of NADK biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of CDON biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of MP2K2 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of H2A3 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of IGFALS biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 20 year period, comprising detecting a level of S100A13 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
The method of any one of the preceding claims, wherein N is 2 to 25, or N is 3 to 25, or N is 4 to 25, or N is 5 to 25, or N is 6 to 25, or N is 7 to 25, or N is 8 to 25, or N is 9 to 25, or N is 10 to 25, or N is 11 to 25, or N is 12 to 25, or N is 13 to 25, or N is 14 to 25, or N is 15 to 25.
The method of any one of the preceding claims, wherein N is 2, N is 3, or N is 4, or N is 5, or N is 6, or N is 7, or N is 8, or N is 9, or N is 10, or N is 11, or N is 12, or N is 13, or N is 14, or N is 15, or N is 16, or N is 17, or N is 18, or N is 19, or N is 20, or N is 21, or N is 22, or N is 23, or N is 24, or N is 25.
The method of any one of the preceding claims, wherein each of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
The method of any one of the preceding claims, wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, and S100A13.
The method of any one of the preceding claims, wherein at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 of the N protein biomarkers are selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are CILP2 and H2A3, or two of the N biomarker proteins are CILP2 and IGFALS, or two of the N biomarker proteins are CILP2 and MP2K2, or two of the N biomarker proteins are CILP2 and NADK, or two of the N biomarker proteins are CILP2 and Notch1, or two of the N biomarker proteins are CILP2 and PH, or two of the N biomarker proteins are CILP2 and PTN, or two of the N biomarker proteins are CILP2 and S100A13, or two of the N biomarker proteins are CILP2 and CDON.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are PTN and PH, or two of the N biomarker proteins are PTN and S100A13, or two of the N biomarker proteins are PTN and Notch1, or two of the N biomarker proteins are PTN and NADK, or two of the N biomarker proteins are PTN and MP2K2, or two of the N biomarker proteins are PTN and IGFALS, or two of the N biomarker proteins are PTN and H2A3, or two of the N biomarker proteins are PTN and CDON.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are PH and Notch1, or two of the N biomarker proteins are PH and NADK, or two of the N biomarker proteins are PH and CDON, or two of the N biomarker proteins are PH and MP2K2, or two of the N biomarker proteins are PH and H2A3, or two of the N biomarker proteins are PH and IGFALS, or two of the N biomarker proteins are PH and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are Notch1 and NADK, or two of the N biomarker proteins are Notch1 and CDON, or two of the N biomarker proteins are Notch1 and MP2K2, or two of the N biomarker proteins are Notch1 and H2A3, or two of the N biomarker proteins are Notch1 and IGFALS, or two of the N biomarker proteins are Notch1 and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are NADK and CDON, or two of the N biomarker proteins are NADK and MP2K2, or two of the N biomarker proteins are NADK and H2A3, or two of the N biomarker proteins are NADK and IGFALS, or two of the N biomarker proteins are NADK and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are CDON and MP2K2, or two of the N biomarker proteins are CDON and H2A3, or two of the N biomarker proteins are CDON and IGFALS, or two of the N biomarker proteins are CDON and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are MP2K2 and H2A3, or two of the N biomarker proteins are MP2K2 and IGFALS, or two of the N biomarker proteins are MP2K2 and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are H2A3 and IGFALS, or two of the N biomarker proteins are H2A3 and S100A13.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are IGFALS and S100A13.
The method of any one of the preceding claims, wherein the sample is a blood sample, a plasma sample, or a serum sample.
The method of any one of the preceding claims, wherein the subject is 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65 years of age or older.
The method of any one of the preceding claims, wherein detecting is performed using mass spectrometry, an aptamer based assay and/or an antibody based assay.
The method of any one of the preceding claims, wherein the method comprises contacting biomarker proteins of the sample or samples with a set of biomarker capture reagents, wherein each biomarker capture reagent of the set of biomarker capture reagents specifically binds to a different biomarker protein being detected.
The method of any one of the preceding claims, wherein determining the risk for developing dementia within a 20 year period is based on input of the levels of the N biomarker proteins measured in a statistical model.
The method of any one of the preceding claims, wherein the subject is identified as at risk for developing dementia within the 20 year period.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of CILP2 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from PTN, PH, Notch1, NADK, CDON, MP2k2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of PTN biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of PH biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of Notch1 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, NADK, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of NADK biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, CDON, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of CDON biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, MP2K2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of MP2K2 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of H2A3 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of IGFALS biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
A method of determining whether a subject is at risk for developing dementia within a 5, 10, and/or 15 year period, comprising detecting a level of S100A13 biomarker protein and a level of each of N biomarker proteins in a sample from the subject, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker proteins is selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2K2, H2A3, IGFALS, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
The method of any one of the preceding claims, wherein two of the N biomarker proteins are Notch1 and NADK, or two of the N biomarker proteins are Notch1 and CDON, or two of the N biomarker proteins are Notch1 and MP2K2, or two of the N biomarker proteins are Notch1 and H2A3, or two of the N biomarker proteins are Notch1 and IGFALS, or two of the N biomarker proteins are Notch1 and S100A13.
The method of any one of the preceding claims, wherein the subject is identified as at risk for developing dementia within the 5, 10, and/or 15 year period.
A kit comprising N biomarker protein capture reagents, wherein N is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, and wherein at least one of the N biomarker protein capture reagents specifically binds to a biomarker protein selected from CILP2, PTN, PH, Notch1, NADK, CDON, MP2k2, H2A3, IGFALS, S100A13, NPTXR, TBCA, CDCP1, sRAGE, SVEP1, NDST1, ASB9, NFL, PARC, TIM-1, calgranulin B, YKL-40, IL-18, ATS13, and OPG.
Dependencies are inferred from the claim text.