US2014315742A1PendingUtilityA1
Biodosimetry panels and methods
Assignee: MESO SCALE TECHNOLOGIES LLCPriority: Sep 29, 2011Filed: Sep 28, 2012Published: Oct 23, 2014
Est. expirySep 29, 2031(~5.2 yrs left)· nominal 20-yr term from priority
Inventors:William F. BlakelyEli N. GlezerJohn KentenSudeep KumarAnu MathewNatalia I. OssetrovaGeorge Sigal
G01N 2800/40G01N 2800/60G01N 2333/70535G01N 2333/70578G01N 33/6893G01T 1/02G01N 33/566G01N 27/3273G01N 35/00G16H 20/40G01T 1/00
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Claims
Abstract
The present invention relates to methods and kits to assess an absorbed dose of ionizing radiation and/or the severity of tissue injury from radiation in a patient. The invention also relates to algorithms used to calculate an absorbed dose of radiation based on biomarker measurements of a plurality of biomarkers that are altered relative to a normal control in the event of radiation exposure.
Claims
exact text as granted — not AI-modified1 . A multiplexed assay kit used to assess an absorbed dose of ionizing radiation or radiation-induced tissue injury in a patient sample, wherein said kit is configured to measure the level of a plurality of biomarkers in said sample and said plurality of biomarkers comprises:
(a) a DNA-damage biomarker; (b) an inflammatory-response biomarker; (c) a tissue-damage biomarker; (d) a tissue-damage repair biomarker; (e) a hematology-surrogate marker; and (f) combinations thereof.
2 . The kit of claim 1 wherein said plurality of biomarkers comprises at least two of biomarkers (a)-(e).
3 . The kit of claim 1 wherein said plurality of biomarkers comprises at least four of biomarkers (a)-(e).
4 . The kit of claim 1 wherein said plurality of biomarker is selected from the group consisting of:
(a) a DNA-damage biomarker;
(b) an inflammatory-response biomarker;
(c) a tissue-damage biomarker;
(d) a tissue-damage repair biomarker; and
(e) a hematology-surrogate marker.
5 . The kit of claim 1 further comprising instructions for correlating the level of said plurality of biomarkers present in the sample with the dose of radiation absorbed by the patient.
6 . The kit of claim 1 further comprising a computer readable medium having stored thereon a computer program which, when executed by a computer system, causes the computer system to perform a method comprising correlating the level of said plurality of biomarkers present in the sample with the dose of radiation absorbed by the patient.
7 . A device capable of receiving the kit of claim 1 or a component thereof to measure level of said plurality of biomarkers, said device operatively associated with a computer system, said computer system having stored thereon a computer program which, when executed by said computer system, causes the computer program to perform a method comprising correlating the level of said plurality of biomarkers present in the sample with the dose of radiation absorbed by the patient.
8 . The kit of claim 1 wherein said inflammatory-response biomarker is not a tissue damage repair biomarker.
9 . The kit of claim 1 wherein said inflammatory-response biomarker is a tissue-damage repair biomarker.
10 . The kit of claim 1 wherein said DNA-damage biomarker comprises p53, p21, GADD45a, ATM, phosphorylated H2AX histone, and combinations thereof.
11 . The kit of claim 1 wherein said inflammatory-response biomarker comprises IL-6, CRP, SAA, IL-1, IL-5, IL-10, KC/GRO, IFN, IL-2, IL-4, TNF-alpha, IL-12, IL-3, IL-7, IL-6, and combinations thereof.
12 . The kit of claim 1 wherein said tissue-damage biomarker comprises salivary beta-amylase, citrulinated proteins, S100B, SP-D, BPI, TSP, CA15-3, CDBB, CKMB, CKMM, FABP2, GFAP, NSE, and combinations thereof.
13 . The kit of claim 1 wherein said hematology-surrogate marker comprises CD5, CD-16b, CD20, CD177, CD26, CD27, CD40, CD45, and combinations thereof.
14 . The kit of claim 1 wherein said tissue damage repair biomarker comprises Flt-3L, G-CSF, KFG, EPO, TPO, GM-CSF, SDF-1a, and combinations thereof.
15 . The kit of claim 1 wherein said tissue-damage repair biomarker is Flt-3L.
16 . The kit of claim 1 further comprising an additional tissue-damage repair biomarker selected from G-CSF, EPO, GM-CSF, SDF-1a, and combinations thereof.
17 . The kit of claim 15 , wherein said inflammatory-response biomarker is IL-12, IL-3, IL-7, IL-6 or combinations thereof.
18 . The kit of claim 1 , wherein said kit comprises Flt-3L, G-CSF, GM-CSF, EPO, CD27, CD45, SAA, CD26, IL-12, and TPO.
19 . The kit of claim 1 wherein said kit comprises Flt-3L, GM-CSF, SAA, TPO, CD27, CD45, CD26, and IL-12.
20 . The kit of claim 1 further comprising an additional kit component comprising (a) a bar-coded patient identification tag; (b) a dried blood spot collection card comprising a bar code; (c) a sample transport bag comprising desiccant; (d) a capillary with a plunger; or (e) a lancet.
21 . The kit of claim 1 wherein said kit is configured to measure said level using an immunoassay.
22 . The kit of claim 21 wherein said kit comprises a multi-well assay plate comprising a plurality of assay wells used in an assay conducted in said kit, said plurality of assay wells configured to measure said level of said plurality of biomarkers in said sample.
23 . The kit of claim 22 wherein a well of said assay plate comprises a plurality of assay domains, at least two of said assay domains comprising reagents for measuring different biomarkers.
24 . The kit of claim 22 wherein said kit comprises an assay cartridge for conducting a plurality of assays, said cartridge comprising a flow cell having an inlet, an outlet or a detection chamber, said inlet, detecting chamber, or outlet defining a flow path through said flow cell, said detection chamber configured to measure said level of said plurality of biomarkers in said sample.
25 . The kit of claim 1 wherein said kit further comprises one or more additional assay reagents used in said assay, said one or more additional assay reagents provided in one or more vials, containers, or compartments of said kit.
26 . The kit of claim 21 wherein said kit further comprises an electrochemiluminescence (ECL) labeling reagent and said levels are measured in an assay conducted with said kit by measuring ECL.
27 . The device of claim 7 wherein said device is configured to conduct an ECL measurement using said kit.
28 . A multiplexed assay kit used to assess an absorbed dose of ionizing radiation in a patient sample, said kit is configured to measure the level of a plurality of biomarkers in said sample, said plurality of biomarkers comprising (i) one or more biomarkers including Flt-3L, G—CSF, GM-CSF, EPO, CD27, CD45, SAA, CD26, IL-12, TPO, and combinations thereof; and (ii) an additional biomarker comprising:
(a) a DNA-damage biomarker;
(b) an inflammatory-response biomarker;
(c) a tissue-damage biomarker;
(d) a tissue-damage repair biomarker;
(e) a hematology-surrogate marker; and
(f) combinations thereof.
29 . The kit of claim 28 wherein said plurality of biomarkers comprises at least two of biomarkers (a)-(e).
30 . The kit of claim 28 wherein said plurality of biomarkers comprises at least four of biomarkers (a)-(e).
31 . The kit of claim 28 wherein said plurality of biomarker is selected from the group consisting of:
(a) a DNA-damage biomarker;
(b) an inflammatory-response biomarker;
(c) a tissue-damage biomarker;
(d) a tissue-damage repair biomarker; and
(e) a hematology-surrogate marker.
32 . The kit of claim 28 further comprising instructions for correlating the level of said plurality of biomarkers present in the sample with the dose of radiation absorbed by the patient.
33 . The kit of claim 28 further comprising a computer readable medium having stored thereon a computer program which, when executed by a computer system, causes the computer system to perform a method comprising correlating the level of said plurality of biomarkers present in the sample with the dose of radiation absorbed by the patient.
34 . A device capable of receiving the kit of claim 28 or a component thereof to measure level of said plurality of biomarkers, said device operatively associated with a computer system, said computer system having stored thereon a computer program which, when executed by said computer system, causes the computer program to perform a method comprising correlating the level of said plurality of biomarkers present in the sample with the dose of radiation absorbed by the patient.
35 . The kit of claim 28 wherein said inflammatory-response biomarker is not a tissue damage repair biomarker.
36 . The kit of claim 28 wherein said inflammatory response biomarker is a tissue-damage repair biomarker.
37 . The kit of claim 28 wherein said DNA-damage biomarker comprises p53, p21, GADD45a, ATM, phosphorylated H2AX histone, and -combinations thereof.
38 . The kit of claim 28 wherein said inflammatory-response biomarker comprises IL-6, CRP, SAA, IL-1, IL-5, IL-10, KC/GRO, IFN, IL-2, IL-4, TNF-alpha, IL-12, IL-3, IL-7, IL-6 and combinations thereof.
39 . The kit of claim 28 wherein said tissue-damage biomarker comprises salivary beta-amylase, citrulinated proteins, S100B, SP-D, BPI, TSP, CA15-3, CKBB, CKMB, CKMM, FABP2, GFAP, NSE, and combinations thereof.
40 . The kit of claim 28 wherein said hematology-surrogate marker comprises CD5, CD-16b, CD20, CD177, CD26, CD27, CD40, CD45, and combinations thereof.
41 . The kit of claim 28 wherein said one or more biomarkers comprise Flt-3L.
42 . The kit of claim 41 wherein said one or more biomarkers further comprise G-CSF, GM-CSF, EPO, CD27, CD45, SAA, CD26, IL-12, and TPO.
43 . The kit of claim 42 , wherein said kit comprises Flt-3L, GM-CSF, SAA, TPO, CD27, CD45, CD26, and IL-12.
44 . The kit of claim 28 further comprising an additional kit component comprising (a) a bar-coded patient identification tag; (b) a dried blood spot collection card comprising a bar code; (c) a sample transport bag comprising desiccant; (d) a capillary with a plunger; or (e) a lancet.
45 . The kit of claim 28 wherein said kit is configured to measure said level using an immunoassay.
46 . The kit of claim 45 wherein said kit comprises a multi-well assay plate comprising a plurality of assay wells used in an assay conducted in said kit, said plurality of assay wells configured to measure said level of said plurality of biomarkers in said sample.
47 . The kit of claim 46 wherein a well of said assay plate comprises a plurality of assay domains, at least two of said assay domains comprising reagents for measuring different biomarkers.
48 . The kit of claim 45 wherein said kit comprises an assay cartridge for conducting a plurality of assays, said cartridge comprising a flow cell having an inlet, an outlet or a detection chamber, said inlet, detecting chamber, and outlet defining a flow path through said flow cell, said detection chamber configured to measure said level of said plurality of biomarkers in said sample.
49 . The kit of claim 28 wherein said kit further comprises one or more additional assay reagents used in said assay, said one or more additional assay reagents provided in one or more vials, containers, or compartments of said kit.
50 . The kit of claim 28 wherein said kit further comprises an electrochemiluminescence (ECL) labeling reagent and said levels are measured in an assay conducted with said kit by measuring ECL.
51 . A multiplexed hematology surrogate biomarker assay kit configured to measure a level of a plurality of biomarkers in a sample, said plurality of biomarkers comprises a lymphocyte cell surface marker, a neutrophil cell surface marker, and combinations thereof.
52 . The kit of claim 51 wherein said lymphocyte surface marker comprising CD5, CD20, CD26, CD27, CD40, and combinations thereof.
53 . The kit of claim 51 wherein said neutrophil cell surface marker comprising CD16b, CD177, and combinations thereof.
54 . The kit of claim 51 wherein said sample is blood cell pellets, serum or plasma.
55 . The kit of claim 1 further comprising an additional kit component comprising (a) a bar-coded patient identification tag; (b) a dried blood spot collection card comprising a bar code; (c) a sample transport bag comprising desiccant; (d) a capillary with a plunger; or (e) a lancet.
56 . The kit of claim 51 wherein said kit is configured to measure said level using an immunoassay.
57 . The kit of claim 56 wherein said kit comprises a multi-well assay plate comprising a plurality of assay wells used in an assay conducted in said kit, said plurality of assay wells configured to measure said level of said plurality of biomarkers in said sample.
58 . The kit of claim 57 wherein a well of said assay plate comprises a plurality of assay domains, at least two of said assay domains comprising reagents for measuring different biomarkers.
59 . The kit of claim 56 wherein said kit comprises an assay cartridge for conducting a plurality of assays, said cartridge comprising a flow cell having an inlet, an outlet or a detection chamber, said inlet, detecting chamber, or outlet defining a flow path through said flow cell, said detection chamber configured to measure said level of said plurality of biomarkers in said sample.
60 . A method of assaying peripheral blood leukocyte status in a sample comprising
(a) measuring a level of a plurality of hematology surrogate biomarkers in a sample, said plurality of biomarkers comprises a lymphocyte cell surface marker, a neutrophil cell surface marker, and combinations thereof; (b) comparing said level of said biomarkers in said sample to a level of said biomarkers in a normal control sample; and (c) determining said peripheral blood leukocyte status based on said comparison step (b).
61 . The method of claim 60 wherein said lymphocyte surface marker comprising CD5, CD20, CD26, CD27, CD40, and combinations thereof.
62 . The method of claim 60 wherein said neutrophil cell surface marker comprising CD16b, CD 177, and combinations thereof.
63 . The method of claim 60 wherein said sample is blood cell pellets, serum or plasma.
64 . The method of claim 60 wherein said sample is plasma.
65 . A method of assessing an absorbed dose of ionizing radiation in a plasma sample from a patient, said method comprising
(a) measuring the level of a hematology surrogate marker in said sample; (b) applying, by a processor, an algorithm to assess said absorbed dose in said patient based on said level of said hematology surrogate marker in said sample.
66 . The method of claim 65 wherein said hematology-surrogate marker comprises CD5, CD-16b, CD20, CD177, CD26, CD27, CD40, CD45 and combinations thereof.
67 . The method of claim 65 wherein said algorithm quantifies an absorbed dose of ionizing radiation in the range of about 1-10 Gy.
68 . A computer readable medium having stored thereon a computer program which, when executed by a computer system operably connected to an assay system configured to measure a level of a plurality of biomarkers in a patient sample, causes the computer system to perform a method of calculating radiation dose by a method comprising:
(a) fitting said measured level to a response surface model as a function of radiation dose or time; (b) computing a cost function for combining said plurality of biomarkers; and (c) selecting a radiation dose that minimizes said cost function at a known time interval.
69 . The computer readable medium of claim 68 wherein said method further comprises the step of (e) comparing said radiation dose to a threshold value above which is indicative of radiation exposure.
70 . The computer readable medium of claim 68 wherein said computing step (b) further comprises applying a weighting function, W i (radiation dose, time), wherein W i is the weighting function of biomarker i as a function of radiation dose or time.
71 . The computer readable medium of claim 68 wherein said cost function represents the total error for said plurality of biomarkers as a function of radiation dose.
72 . The computer readable medium of claim 68 wherein said cost function is
F
(
dose
)
=
∑
i
=
1
n
Log
(
m
i
+
LOD
i
M
i
(
dose
)
+
LOD
i
)
,
wherein m i is the measured value for biomarker i, M i is the predicted biomarker value as a function of dose at a known time post-exposure, LOD i is the assay Limit of Detection for biomarker i, or n is the total number of biomarkers being used.
73 . The computer readable medium of claim 68 wherein said cost function is:
F
(
dose
)
=
∑
i
=
1
n
Log
(
m
i
M
i
(
dose
)
)
.
wherein m i is the measured value for biomarker i, M i is the predicted biomarker value as a function of dose at a known time post-exposure, or n is the total number of biomarkers being used.
74 . The method of claim 65 wherein the sample comprises plasma.Join the waitlist — get patent alerts
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