WO2016160484A1 - Nouveaux biomarqueurs pour troubles psychiatriques - Google Patents

Nouveaux biomarqueurs pour troubles psychiatriques Download PDF

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Publication number
WO2016160484A1
WO2016160484A1 PCT/US2016/023915 US2016023915W WO2016160484A1 WO 2016160484 A1 WO2016160484 A1 WO 2016160484A1 US 2016023915 W US2016023915 W US 2016023915W WO 2016160484 A1 WO2016160484 A1 WO 2016160484A1
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test
level
combined score
test level
biomarkers
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PCT/US2016/023915
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English (en)
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Rajesh KALDATE
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Myriad Genetics, Inc.
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Publication of WO2016160484A1 publication Critical patent/WO2016160484A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/302—Schizophrenia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis

Definitions

  • This disclosure relates to biomarkers and methods of diagnosing or monitoring bipolar disorder, schizophrenia, schizoaffective disorder and prodromal syndrome, or a predisposition thereto.
  • prodromal schizophrenia also referred to as ultra-high risk syndrome
  • the prodromal syndrome is characterized on the basis of structured clinical interviews, which evaluate disturbances in perception, thought processing, language and attention (Fusar-Poli P. et al. (2014) Annu. Rev. Clin. Psychol.).
  • One aspect of the disclosure provides a method of diagnosing bipolar disorder ("BPD") comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from IGFBP1, LH, IL8, vWF, MMP1, IL2ra, AFP, and CD40, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having BPD based at least in part on the results of the comparison in (2).
  • BPD bipolar disorder
  • Another aspect of the disclosure provides a method of diagnosing schizophrenia ("SCZ") comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from IGFBP1, LH, IL8, vWF, TTR, tPA, MDC, PARC, IL16, TNFR2, AlMicro, and SAP, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having SCZ based at least in part on the results of the comparison in (2).
  • SCZ schizophrenia
  • Another aspect of the disclosure provides a method of diagnosing schizoaffective disorder ("SAD") comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from IGFBP1, MMP1, TTR, ApoD, MMP7, IGFBP6, uPAR, ApoH, CRP, and ApoCI, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having SAD based at least in part on the results of the comparison in (2).
  • SAD schizoaffective disorder
  • Another aspect of the disclosure provides a method of diagnosing prodromal syndrome ("PRD") comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from tPA, ApoA-IV, TSH, FRTN, PAI1, CathepsinD, ApoA- II, Total Testosterone, MSP, IL12p40, CLU, ErbB3, Apolipo-a, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having PRD based at least in part on the results of the comparison in (2).
  • PRD prodromal syndrome
  • Another aspect of the disclosure provides a method of differentiating between BPD and SAD comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from tPA, ApoD, IL13, Gelsolin, IL23, IGFBP6, and CRP, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having either BPD or SAD based at least in part on the results of the comparison in (2).
  • test biomarkers chosen from tPA, ApoD, IL13, Gelsolin, IL23, IGFBP6, and CRP
  • Another aspect of the disclosure provides a method of differentiating between BPD and SCZ comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from IL2ra, ApoD, IL13, Gelsolin, IGFBP6, MlPlbeta, ApoE, FiblC, and HER2, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having either BPD or SCZ based at least in part on the results of the comparison in (2).
  • test biomarkers chosen from IL2ra, ApoD, IL13, Gelsolin, IGFBP6, MlPlbeta, ApoE, FiblC, and HER2, or any combination of two or more of said test biomarkers
  • Another aspect of the disclosure provides a method of differentiating between SCZ and SAD comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from IGFBP1, IL8, ApoH, MlPlbeta, ApoE, FiblC, ApoA-l, Sortilin, HB-EGF, C3, FAS, ACE, Ckine, and IGFBP4, or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having either SCZ or SAD based at least in part on the results of the comparison in (2).
  • test biomarkers chosen from IGFBP1, IL8, ApoH, MlPlbeta, ApoE, FiblC, ApoA-l, Sortilin, HB-EGF, C3, FAS, ACE, Ckine, and IGFBP4, or any combination of two or more
  • kits useful in performing methods as described herein.
  • Such kits will generally comprise one or more reagents capable of specifically detecting and/or quantifying each test biomarker whose level is to be determined in the method, optionally together with instructions for use of the kit.
  • Biomarkers for schizophrenia or other psychotic disorder as disclosed herein are essential targets for discovery of novel targets and drug molecules that retard or halt progression of the disorder. As the level of the biomarker is indicative of disorder and of drug response, the biomarker may be useful as described herein for identification of novel therapeutic compounds in in vitro and/or in vivo assays. Biomarkers of the disclosure can be employed in methods for screening for compounds that modulate the activity of the peptide.
  • a further aspect of the disclosure provides methods generally comprising the use of one or more test biomarkers or reagents capable of specifically detecting and/or quantifying said test biomarker(s) (e.g., a kit according to the disclosure) to identify a substance capable of promoting and/or of suppressing the generation of the test biomarker.
  • test biomarkers or reagents capable of specifically detecting and/or quantifying said test biomarker(s) (e.g., a kit according to the disclosure) to identify a substance capable of modifying the underlying disease (e.g., BPD, SCZ, SAD, PRD).
  • a substance capable of modifying the underlying disease e.g., BPD, SCZ, SAD, PRD.
  • a method of identifying a substance capable of promoting or suppressing the generation of the peptide in a subject comprising administering a test substance to a subject animal and detecting and/or quantifying the level of the test biomarker present in a test sample from the subject.
  • a further aspect of the disclosure provides a method for treating schizophrenia according to the above described methods but further comprising the step of administering a drug suitable for the treatment of the specific disease diagnosed.
  • Methods of treatment may comprise treating a patient with anti-psychotic drugs and/or non- drug therapies.
  • results of any analyses according to the disclosure will often be communicated to physicians and/or patients (or other interested parties such as researchers) in a transmittable form that can be communicated or transmitted to any of the above parties. Therefore, a further aspect of the disclosure provides systems for diagnosing and treating schizophrenia. These systems may comprise sample analyzers, computers and software as described herein.
  • Figure 1 presents a heat map of highly correlated set of 52 analytes.
  • Figure 2 presents a distribution of sub-populations in Study 2.
  • First Canonical Axis (1 Dimensional Data Space).
  • Figure 3 presents a distribution of sub-populations in Study 2.
  • Figure 4 presents a distribution of sub-populations in Study 2.
  • Figure 5 presents a distribution of sub-populations in Study 3. Single Canonical Axis (1 Dimensional Data Space).
  • Figure 6 reports the performance of various biomarker models in diagnosing psychiatric disease (generally and specifically) and differentiating specific psychiatric diseases from each other.
  • Figure 7 reports the performance of various biomarker models in diagnosing psychiatric disease (generally and specifically) and differentiating specific psychiatric diseases from each other.
  • Figure 8 reports the performance of various biomarker models in diagnosing psychiatric disease (generally and specifically) and differentiating specific psychiatric diseases from each other.
  • biomarker means a distinctive biological or biologically-derived indicator of a process, event, or condition. Biomarkers can be used in methods of diagnosis, e.g., clinical screening, and prognosis assessment and in monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, drug screening and development. Biomarkers and uses thereof are valuable for identification of new drug treatments and for discovery of new targets for drug treatment.
  • IGFBP6 Insulin-like Growth Factor Binding Protein 6
  • IGFBP6 P24592 ng/mL lnterleukin-12
  • Subunit p40 IL-12p40 P29460 ng/mL lnterleukin-13 IL-13 P35225 pg/mL lnterleukin-16 IL-16
  • Q.14005 pg/mL lnterleukin-2 receptor alpha IL-2ra P01589 pg/mL lnterleukin-23 IL-23 Q9NPF7 ng/mL lnterleukin-8 IL-8 P10145 pg/mL
  • Tumor necrosis factor receptor 2 TNFR2 P20333 ng/mL
  • Urokinase-type plasminogen activator receptor uPAR Q03405 ng/mL von Willebrand Factor vWF P04275 ⁇ g/mL References to each of these biomarkers in this disclosure generally refer to either the relevant full-length protein (e.g., having an amino acid sequence corresponding to the SwissProt number indicated above) or any protein whose amino acid sequence is at least 80% identical to such full-length protein.
  • the diagnostic methods of the disclosure generally involve measuring the levels of particular biomarkers, comparing these levels to reference levels, and diagnosing disease based at least in part on this comparison.
  • the disclosure provides a method of diagnosing BPD, SCZ, SAD, or PRD, the method comprising:
  • diagnosis encompasses identification, confirmation, and/or characterization of BPD, SCZ, SAD or PRD, or increased likelihood of having each or predisposition thereto.
  • prognosis encompasses the prediction of whether a patient is likely to develop schizophrenia or other psychotic disorder. By “predisposition” it is meant that a subject does not currently present with the disorder, but is liable to be affected by the disorder in time.
  • Embodiment 1 provides a method of diagnosing bipolar disorder (“BPD"), the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from AFP, CD40, IGFBPl, IL2ra, IL8, LH, MMPl, and vWF (Panel D from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having BPD based at least in part on the results of the comparison in (2).
  • BPD bipolar disorder
  • Embodiment 2 provides a method of diagnosing schizophrenia (“SCZ"), the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from AlMicro, IGFBP1, IL16, IL8, LH, MDC, PARC, SAP, TNFR2, tPA, TTR, and vWF (Panel E from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having SCZ based at least in part on the results of the comparison in (2).
  • SCZ schizophrenia
  • Embodiment 3 provides a method of diagnosing schizoaffective disorder (“SAD"), the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from ApoC-l, ApoD, ApoH, CRP, IGFBP1, IGFBP6, MMP1, MMP7, TTR, and uPAR (Panel F from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having SAD based at least in part on the results of the comparison in (2).
  • SAD schizoaffective disorder
  • Embodiment 4 provides a method of diagnosing prodromal syndrome (“PRD"), the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from ApoA-ll, ApoA-IV, Apolipoprotein-a, CathepsinD, CLU, ErbB3, FRTN, IL12p40, MSP, PAI1, Total Testosterone, tPA, and TSH (Panel H from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having PRD based at least in part on the results of the comparison in (2).
  • PRD prodromal syndrome
  • biomarker panels of this disclosure have high specificity for each respective psychiatric disorder. Therefore, according to a further aspect of the disclosure, the biomarker panels described herein may be used as a specific panel of biomarkers for the differential diagnosis of a psychiatric disorder described herein from a further psychiatric disorder described herein.
  • the term "differential diagnosis” in this context refers to, e.g., the positive diagnosis of BPD from that of SAD (and vice versa), the positive diagnosis of BPD from that of SCZ (and vice versa), or the positive diagnosis of SCZ from that of SAD (and vice versa).
  • Embodiment 5 provides a method of differentiating between BPD and SAD, the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from ApoD, CRP, Gelsolin, IGFBP6, IL13, IL23, and tPA (Panel A from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having either BPD or SAD based at least in part on the results of the comparison in (2).
  • test biomarkers chosen from ApoD, CRP, Gelsolin, IGFBP6, IL13, IL23, and tPA
  • Embodiment 6 provides a method of differentiating between BPD and SCZ, the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from ApoD, ApoE, FiblC, Gelsolin, HER2, IGFBP6, IL13, I L2ra, and MlPlbeta (Panel B from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having either BPD or SCZ based at least in part on the results of the comparison in (2).
  • test biomarkers chosen from ApoD, ApoE, FiblC, Gelsolin, HER2, IGFBP6, IL13, I L2ra, and MlPlbeta
  • Embodiment 7 provides a method of differentiating between SCZ and SAD, the method comprising (1) determining in a sample obtained from a patient the test level of one or more test biomarkers chosen from ACE, ApoA-l, ApoE, ApoH, C3, Ckine, FAS, FiblC, HB-EGF, IGFBP1, IGFBP4, I L8, MlPlbeta, and Sortilin (Panel C from Figure 8), or any combination of two or more of said test biomarkers; (2) comparing the test level(s) determined in (1) to a reference level of each of said test biomarker(s); and (3) diagnosing said patient as having either SCZ or SAD based at least in part on the results of the comparison in (2). Test and Reference Levels
  • the levels of one or more analyte biomarkers or the levels of a specific panel of analyte biomarkers in a sample are compared to a reference standard ("reference standard” or “reference level”) in order to diagnose disease, direct treatment decisions, etc.
  • the reference standard used for any embodiment disclosed herein may comprise average, mean, or median levels of the one or more analyte biomarkers or the levels of the specific panel of analyte biomarkers in a control population (or, as discussed below, the average, mean, or median or some combined score derived from these levels).
  • the reference standard may additionally comprise cutoff values or any other statistical attribute of the control population, such as a standard deviation from the mean levels of the one or more analyte biomarkers or the levels of the specific panel of analyte biomarkers (e.g., the combined score).
  • comparing the level of one or more analyte biomarkers is performed using a cutoff or threshold value.
  • the individual may be diagnosed as having, or being at risk of developing BPD, SCZ, SAD, and/or PRD.
  • the level of the one or more analyte biomarkers (or a test combined score derived therefrom) is less than the cutoff value, the individual may be diagnosed as having, or being at risk of developing BPD, SCZ, SAD, and/or PRD.
  • the individual may be diagnosed as having one psychiatric disorder (e.g., BPD) if the level of one or more analyte biomarkers (or a test combined score derived therefrom) is greater (or equal to) than the cutoff value and the individual may be diagnosed as having a different psychiatric disorder (e.g., SCZ) if the level of one or more analyte biomarkers (or a test combined score derived therefrom) is less than (or equal to) the cutoff value.
  • one psychiatric disorder e.g., BPD
  • SCZ a different psychiatric disorder
  • Cutoff values may be determined by statistical analysis of the control population to determine which levels (or combined score values) represent a high likelihood that an individual does or does not belong to the control population.
  • comparing the level of the one or more analyte biomarkers (or combined score values) is performed using other statistical methods.
  • comparing comprises logistic or linear regression.
  • comparing comprises computing an odds ratio.
  • control population may comprise healthy individuals or individuals with BPD, SCZ, SAD, or PRD.
  • an individual diagnosed with BPD, SCZ, SAD, or PRD may be identified as a candidate for treatment with a therapeutic agent for the specific disease diagnosed.
  • an individual presenting with levels of one or more analyte biomarkers or levels of the specific panel of analyte biomarkers (or a combined score value derived therefrom) greater than a reference standard associated with SCZ may be identified as a candidate for treatment with an anti-psychotic therapy, or with more aggressive therapy.
  • an individual presenting with levels of the one or more analyte biomarkers or levels of the specific panel of analyte biomarkers (or a combined score derived therefrom) less than or equal to the reference standard associated with SCZ may be identified as a candidate for no anti-psychotic therapy, delayed anti-psychotic therapy or less aggressive anti-psychotic therapy.
  • test e.g., "test” level, “test” combined score, etc.
  • a character e.g., level, combined score, etc.
  • a “test level” in Embodiment 1 can refer to the level of a particular biomarker determined in a sample of a patient for whom a potential diagnosis of BPD is sought.
  • Such "test” characters are distinguished from their corresponding "reference” characters.
  • Reference generally refers to a character general to patients (or samples obtained from patients) known to have a particular disease state or character.
  • the "reference” is a threshold value above which patients are known (or predicted) to have a certain disease or disease character and below which patients are known (or predicted) to either not have such disease or disease character or to have a disease or disease character different from the first.
  • a "reference level" in Embodiment 1 can refer to the level of a particular biomarker known (e.g., according to the present disclosure) to be associated with BPD (e.g., in a reference cohort of patients).
  • a "reference level” in Embodiment 1 can refer to a threshold level of a particular biomarker where test levels above such threshold are known (e.g., according to the present disclosure) to be associated with BPD (e.g., in a reference cohort of patients) and test levels below such threshold are known (e.g., according to the present disclosure) to be associated with the absence of BPD (e.g., in a reference cohort of patients).
  • the "level" of a biomarker refers to the amount or concentration of such biomarker within a certain sample. It should be noted that references to biomarker amounts or levels can in some embodiments also include a biomarker range. Determining the level of a biomarker also includes determining whether or not the biomarker is present (i.e., includes a failure to detect the biomarker). I n some embodiments of the disclosure the level of a biomarker can be the raw amount of the biomarker in a sample (e.g., number of molecules, mass of biomarker in the sample, etc.).
  • the level of a biomarker can be the concentration of the biomarker in the sample (e.g., number of molecules or mass of biomarker per volume of sample, etc.).
  • the unit of measurement for concentration for any of the markers of the disclosure is chosen from mg/dL, mg/mL, ml U/mL, ng/mL, pg/mL, ⁇ g/mL, and ⁇ /mL.
  • the unit of measurement of concentration for each biomarker of the disclosure is as shown in Table 1 above.
  • the "level" of a biomarker can be (a) the raw amount or concentration of the biomarker in a sample as discussed above or (b) scores or other variables normalized or derived from this raw amount or concentration.
  • the test level of a biomarker is the raw amount of the biomarker mathematically manipulated in some way (sometimes referred to herein as a "derived level"). I n some such embodiments the test level or test derived level is obtained by taking the logio of the concentration. In other embodiments the test level or test derived level is obtained by multiplying the concentration by a coefficient. In some embodiments the test level or test derived level is obtained by taking the logio of the concentration and multiplying this by a coefficient.
  • test derived levels for each biomarker in the panel are combined (e.g., added to each other) to yield a test combined score for the sample that may be compared to a reference combined score that analogously represents the combination of reference derived levels for each biomarker.
  • this comparison e.g., the test combined score against the reference combined score
  • step (1) comprises (l)(a) determining the level of each test biomarker in said sample and (l)(b) calculating a test derived level of each such test biomarker; and wherein step (2) comprises comparing said test derived level to a reference derived level of said test biomarker.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said derived combined score to a reference combined score.
  • step (2) comprises comparing said derived combined score to a reference combined score.
  • step 10 provides a method of Embodiment 9, wherein step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Combined Score (A ⁇ ftest level of [test biomarkerji)) + (A 2 *(test level of [test biomarker] 2 )) + (A 3 *(test level of [test biomarker] 3 )) + ... + (A n *(test level of [test biomarkerjn)); wherein the test levels of at least n biomarkers according any of Embodiments 1 to 7 (e.g., biomarkers in any one of Panels A to H in Figure 8) are combined.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said derived combined score to a reference combined score.
  • Embodiment 12 provides a method of Embodiment 11, wherein step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Test Combined Score (A* (test level of AFP)) + (B*(test level of CD40)) + (C*(test level of lGFBPl)) + (D*(test level of IL2ra)) + (E*(test level of 118)) + (F*(test level of LH)) + (G*(test level of MMPl)) + (H*(test level of vWF)).
  • Embodiment 15 provides a method of any of Embodiments 11 to 14, wherein step (3) comprises diagnosing said patient as having BPD based at least in part on said test combined score being less than or equal to said reference combined score.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said test combined score to a reference combined score.
  • step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Test Combined Score (A* (test level of AlMicro)) + (B*(test level of IGFBP1)) + (C*(test level of 1116)) + (D*(test level of 118)) + (E*(test level of LH)) + (F*(test level of MDC)) + (G*(test level of PARC)) + (H*(test level of SAP)) + (I* (test level of TNFR2)) + (J*(test level of tPA)) + (K*(test level of TTR)) + (L*(test level of vWF)).
  • Embodiment 20 provides a method of any of Embodiments 16 to 19, wherein step (3) comprises diagnosing said patient as having SCZ based at least in part on said test combined score being less than or equal to said reference combined score.
  • step 21 provides a method of Embodiment 3, wherein step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said test combined score to a reference combined score.
  • step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Test Combined Score (A*(test level of ApoC-l)) + (B*(test level of ApoD)) + (C*(test level of ApoH)) + (D*(test level of CRP)) + (E*(test level of IGFBP1)) + (F*(test level of IGFBP6)) + (G*(test level of MMP1)) + (H*(test level of MMP7)) + (l*(test level of TTR)) + (J*(test level of uPAR)).
  • Embodiment 25 provides a method of any of Embodiments 21 to 24, wherein step (3) comprises diagnosing said patient as having SAD based at least in part on said test combined score being less than or equal to said reference combined score.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said derived combined score to a reference combined score.
  • step (2) comprises comparing said derived combined score to a reference combined score.
  • step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Test Combined Score (A* (test level of ApoA-ll)) + (B*(test level of ApoA-IV)) + (C*(test level of Apolipoprotein-a)) + (D*(test level of CathepsinD)) + (E*(test level of CLU)) + (F*(test level of ErbB3)) + (G*(test level of FRTN)) + (H*(test level of IL12p40)) + (l*(test level of MSP)) + (J*(test level of P All)) + (K*(test level of Total Testosterone)) + (L*(test level of tPA)) + (M*(test level of TSH)).
  • Embodiment 30 provides a method of any of Embodiments 26 to 29, wherein step (3) comprises diagnosing said patient as having PRD based at least in part on said test combined score being less than or equal to said reference combined score.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said derived combined score to a reference combined score.
  • step (3) comprises either (3)(a) diagnosing said patient as having BPD based at least in part on said test combined score exceeding said reference combined score or (3)(b) diagnosing said patient as having SAD based at least in part on said test combined score being equal to or less than said reference combined score.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said derived combined score to a reference combined score.
  • Embodiment 37 provides a method of Embodiment 36, wherein step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Test Combined Score (A*(test level of ApoD)) + (B*(test level of ApoE)) + (C*(test level of FiblC)) + (D*(test level of Gelsolin)) + (E*(test level of HER2)) + (F*(test level of IGFBP6)) + (G*(test level of 1113)) + (H*(test level of IL2ra)) + (l*(test level of MlPlbeta)).
  • step (3) comprises either (3)(a) diagnosing said patient as having BPD based at least in part on said test combined score exceeding said reference combined score or (3)(b) diagnosing said patient as having SCZ based at least in part on said test combined score being equal to or less than said reference combined score.
  • step (1) comprises (l)(a) determining the test level of each of a plurality of said test biomarkers in said sample and (l)(b) combining said test levels to yield a test combined score; and wherein step (2) comprises comparing said derived combined score to a reference combined score.
  • Embodiment 42 provides a method of Embodiment 41, wherein step (l)(b) comprises combining said test levels to yield a test combined score according to the following equation:
  • Test Combined Score (A*(test level of ACE)) + (B*(test level of ApoA-l)) + (C*(test level ofApoE)) + (D*(test level ofApoH)) + (E*(test level of C3)) + (F*(test level of Ckine)) + (G*(test level of FAS)) + (H*(test level of FiblC)) + (l*(test level of HB-EGF)) + (J*(test level of IGFBP1)) + (K*(test level of IGFBP4)) + (L*(test level of 118)) + (M*(test level of MlPlbeta)) + (N*(test level ofSortilin)).
  • Embodiment 45 provides a method of any of Embodiments 41 to 44, wherein step (3) comprises either (3)(a) diagnosing said patient as having SAD based at least in part on said test combined score exceeding said reference combined score or (3)(b) diagnosing said patient as having SCZ based at least in part on said test combined score being equal to or less than said reference combined score.
  • references herein to "difference in the level,” one value “exceeding" another, or one value being “less than” another each respectively refers to either a higher or lower value compared with one or more reference values.
  • a higher or lower value is a ⁇ 1 fold difference relative to a reference, such as a fold difference of 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.01 or any ranges therebetween.
  • a lower value is between a 0.1 and 0.9 fold difference, such as between a 0.2 and 0.5 fold difference, relative to a reference.
  • a higher or lower value is a > 1 fold difference relative to a reference, such as a fold difference of 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 15 or 20 or any ranges therebetween.
  • a higher value is between a 1 and 15 fold difference, such as between a 2 and 10 fold difference, relative to a reference.
  • the individual is a drug naive patient (e.g., a first onset drug-naive patient).
  • the individual is first-onset or recent-onset drug naive patient.
  • the individual is an un-medicated patient. It will be understood that the term "drug naive" patients includes patients which have not previously been diagnosed or medicated for the particular psychiatric disorder.
  • un-medicated refers to patients which have not been taking medication for the particular psychiatric disorder (e.g., anti-psychotic medication) for at least 1 year, for example for at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 years, in particular for at least 3 years.
  • psychiatric disorder e.g., anti-psychotic medication
  • Prodromal syndrome refers to the period of decreased functioning in a patient that precedes the onset of schizophrenia. Prodromal syndrome may be diagnosed on the basis of structured clinical interviews (see Fusar-Poli P. et al. (2014) Annu. Rev. Clin. Psychol.).
  • a method of monitoring efficacy of a therapy in a subject having, suspected of having, or of being predisposed to BPC, SCZ, SAD or PRD comprising detecting and/or quantifying, in a sample from said subject, the analyte biomarkers as described herein.
  • Monitoring methods of the disclosure can be used to monitor onset, progression, stabilization, amelioration and/or remission.
  • detecting and/or quantifying the biomarker in a biological sample from a test subject may be performed on two or more occasions. Comparisons may be made between the level of biomarker in samples taken on two or more occasions. Assessment of any change in the level of the biomarker in samples taken on two or more occasions may be performed. Modulation of the biomarker level is useful as an indicator of the state of schizophrenia or other psychotic disorder or predisposition thereto.
  • An increase (or in some cases a decrease) in the level of the biomarker over time may be indicative of onset or progression, i.e., worsening of this disorder, whereas a decrease (or in some cases an increase) in the level of the biomarker may be indicative of amelioration or remission of the disorder.
  • the biomarker panels described herein may be used in conjunction with current methods of diagnosis (e.g., structured interviews and/or psychiatric assessment). The use of both tests will aid in earlier and more accurate diagnosis of schizophrenia.
  • the biomarker panel described herein may be used in conjunction with the Comprehensive Assessment of At-Risk Mental State (CAARMS).
  • CAARMS Comprehensive Assessment of At-Risk Mental State
  • Also provided is a method of monitoring efficacy of a therapy for BPD, SCZ, SAD or PRD in a subject having such a disorder, suspected of having such a disorder, or of being predisposed thereto, comprising detecting and/or quantifying the biomarker present in a biological sample from said subject.
  • test samples may be taken on two or more occasions.
  • the method may further comprise comparing the level of the biomarker present in the test sample with one or more reference(s) and/or with one or more previous test sample(s) taken earlier from the same test subject, e.g., prior to commencement of therapy, and/or from the same test subject at an earlier stage of therapy.
  • the method may comprise detecting a change in the level of the biomarker in test samples taken on different occasions.
  • the method comprises comparing the amount of biomarker(s) in said test biological sample with the amount present in one or more samples taken from said individual prior to commencement of treatment, and/or one or more samples taken from said individual during treatment.
  • Methods of monitoring and of diagnosis or prognosis according to the disclosure are useful to confirm the existence of a disorder, or predisposition thereto; to monitor development of the disorder by assessing onset and progression, or to assess amelioration or regression of the disorder. Methods of monitoring and of diagnosis or prognosis are also useful in methods for assessment of clinical screening, choice of therapy, evaluation of therapeutic benefit, e.g., for drug screening and drug development.
  • Methods for monitoring efficacy of a therapy can be used to monitor the therapeutic effectiveness of existing therapies and new therapies in human subjects and in non- human animals (e.g., in animal models). These monitoring methods ca n be incorporated into screens for new drug substances and combinations of substances.
  • the time elapsed between taking samples from a subject undergoing diagnosis or monitoring may be 3 days, 5 days, a week, two weeks, a month, 2 months, 3 months, 6 or 12 months. Samples may be taken prior to and/or during and/or following therapy for schizophrenia. Samples can be taken at intervals over the remaining life, or a part thereof, of a subject.
  • the method additionally comprises administering a therapeutic regimen to an individual who is diagnosed with or predicted to have BPD, SCZ, SAD, or PRD.
  • a therapeutic regimen to an individual who is diagnosed with or predicted to have BPD, SCZ, SAD, or PRD.
  • the disclosure provides a method of treating BPD, SCZ, SAD, or PRD, the method comprising:
  • Embodiment 46 provides the method of any of Embodiments 1 to 45, further comprising (4) prescribing, recommending, or administering a therapeutic regimen for BPD, SCZ, SAD, or PRD (e.g., the therapeutic regimens described below) based at least in part on the diagnosis in (3).
  • a therapeutic regimen for BPD, SCZ, SAD, or PRD e.g., the therapeutic regimens described below
  • a patient is treated more or less aggressively than a reference therapy.
  • a reference therapy is any therapy that is the standard of care for schizophrenia.
  • the standard of care can vary temporally and geographically, and a skilled person can easily determine the appropriate standard of care by consulting the relevant medical literature.
  • treatment will be either 1) more aggressive, or 2) less aggressive than a standard therapy.
  • a more aggressive therapy than the standard therapy comprises beginning treatment earlier than in the standard therapy. In some embodiments, a more aggressive therapy than the standard therapy comprises administering additional treatments than in the standard therapy. In some embodiments, a more aggressive therapy than the standard therapy comprises treating on an accelerated schedule compared to the standard therapy. In some embodiments, a more aggressive therapy than the standard therapy comprises administering additional treatments not called for in the standard therapy.
  • a less aggressive therapy than the standard therapy comprises delaying treatment relative to the standard therapy. In some embodiments, a less aggressive therapy than the standard therapy comprises administering less treatment than in the standard therapy. In some embodiments, a less aggressive therapy than the standard therapy comprises administering treatment on a decelerated schedule compared to the standard therapy. In some embodiments, a less aggressive therapy than the standard therapy comprises administering no treatment.
  • SCZ for example, is treated primarily with anti-psychotic medications which are also referred to as neuroleptic drugs or neuroleptics.
  • anti-psychotic medications which are also referred to as neuroleptic drugs or neuroleptics.
  • Newer anti-psychotic agents such as clozapine, olanzapine, quetiapine or risperidone are thought to be more effective in improving negative symptoms of psychotic disorders than older medication like chlorpromazine. Furthermore, they induce less extrapyramidal side effects (EPS) which are movement disorders resulting from anti-psychotic treatment.
  • EPS extrapyramidal side effects
  • an antipsychotic treatment is selected from one or more of: chlorpromazine, haloperidol, trifluoperazine, clozapine, olanzapine, quetiapine or risperidone, in particular, clozapine, olanzapine, quetiapine or risperidone.
  • a practitioner may also treat an individual with non-drug-based therapies.
  • the non-drug based therapy comprises cognitive-behavioral therapy.
  • the non-drug based therapy comprises psychotherapy.
  • the non-drug based therapy comprises psychodynamic therapy.
  • the non-drug based therapy comprises electroconvulsive therapy.
  • the non-drug based therapy comprises hospitalization and residential treatment programs.
  • the non-drug based therapy comprises vagus nerve stimulation.
  • the non-drug based therapy comprises transcranial magnetic stimulation.
  • the practitioner adjusts the therapeutic regimen based on a comparison between a reference level and the levels of one or more analyte biomarkers or the levels of a specific panel of analyte biomarkers in a sample from a patient.
  • the practitioner adjusts the therapy by selecting and administering a different drug ("A” in this paragraph).
  • the practitioner adjusts the therapy by selecting and administering a different combination of drugs ("B” in this paragraph).
  • the practitioner adjusts the therapy by adjusting drug dosage ("C” in this paragraph).
  • the practitioner adjusts the therapy by adjusting dose schedule ("D” in this paragraph).
  • the practitioner adjusts the therapy by adjusting length of therapy ("E” in this paragraph).
  • the practitioner adjusts the therapy by performing (or prescribing or recommending) any of the following combinations: B and C; B and D; B and E; C and D; C and E; D and E; A, C and D; A, C and E; A, D and E; C, D and E; or A, C, D and E.
  • treatment comprises a less aggressive therapy than a reference therapy.
  • a less aggressive therapy comprises not administering drugs and taking a "watchful waiting" approach.
  • a less aggressive therapy comprises delaying treatment ("A” in this paragraph).
  • a less aggressive therapy comprises selecting and administering less potent drugs ("B” in this paragraph).
  • a less aggressive therapy comprises decreasing dosage of drugs ("C” in this paragraph).
  • a less aggressive therapy comprises decreasing the frequency treatment ("D” in this paragraph).
  • a less aggressive therapy comprises shortening length of therapy ("E” in this paragraph).
  • less aggressive therapy comprises any of the following combinations: B and C; B and D; B and E; C and D; C and E; D and E; B, C and D; B, C and E; B, D and E; C, D and E; or B, C, D and E.
  • a less aggressive therapy comprises administering only non-drug-based therapies.
  • treatment comprises a more aggressive therapy than a reference therapy.
  • more aggressive therapy comprises selecting and administering more potent drugs ("A" in this paragraph).
  • a more aggressive therapy comprises earlier administration of anti-psychotic drugs ("B” in this paragraph).
  • a more aggressive therapy comprises increased dosage of anti-psychotic drugs ("C” in this paragraph).
  • a more aggressive therapy comprises increased length of therapy ("D” in this paragraph).
  • a more aggressive therapy comprises increased frequency of the dose schedule ("E” in this paragraph).
  • more aggressive therapy comprises any of the following combinations: A and C; A and E; A and D; C and E; C and D; D and E; A, C and E; A, C and D; A, D and E; C, D and E; or A, C, D and E.
  • a more aggressive therapy comprises administering a combination of drug-based and non-drug-based therapies.
  • Panel G is successful at discriminating psychiatric disease patients (e.g., patients having at least one of BPD, SCZ, SAD or PRD) from healthy controls with a training AUC of 0.94 and a cross validation AUC of 0.94 (see Figure 8).
  • psychiatric disease patients e.g., patients having at least one of BPD, SCZ, SAD or PRD
  • determining encompasses either assaying a sample to detect the level of the biomarker or reviewing the results of such an assay, or both.
  • the term “detecting” as used herein means confirming the presence of the biomarker present in the sample. Because “level” includes both the binary presence or absence as well as the amount of a biomarker, “detecting" the level of a biomarker encompasses confirming the presence of a biomarker and/or quantifying the amount of the biomarker. Quantifying the amount of the biomarker present in a sample may include determining the concentration of the biomarker present in the sample. Detecting and/or quantifying may be performed directly on a sample obtained from a patient (e.g., blood), or indirectly on an extract therefrom (e.g., plasma), or on a dilution thereof.
  • Embodiment 47 provides the method of any of Embodiments 1 to 46, wherein the determining step comprises assaying the sample to measure the level(s) of the one or more biomarkers.
  • the presence of a biomarker is assessed by detecting and/or quantifying the biomarker (e.g., a protein) or a fragment thereof, e.g., a fragment with C- terminal truncation, or with N-terminal truncation.
  • fragments are greater than 4 amino acids in length, for example 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length.
  • the presence of a biomarker is assessed by detecting and/or quantifying antibody or fragments thereof capable of specific binding to the biomarker that are generated by the subject's body in response to the peptide and thus are present in a biological sample from a subject having BPD, SCZ, SAD, or PRD, or a predisposition thereto.
  • Methods of the disclosure ca n be performed in array format, e.g., on a chip, or as a multi-well array. Methods can be adapted into platforms for single tests, or multiple identical or multiple non-identical tests, and can be performed in high throughput format. Methods of the disclosure may comprise performing one or more additional, different tests to confirm or exclude diagnosis, and/or to further characterize a condition.
  • Detecting and/or quantifying can be performed by any method suitable, in view of the present disclosure, to identify the presence and/or amount of the specific biomarkers of the disclosure in a biological sample from a patient or a purification or extract of a biological sample or a dilution thereof.
  • quantifying may be performed by measuring the concentration of the biomarker in the sample or samples.
  • Biological samples that may be tested in a method of the disclosure include whole blood, blood serum, plasma, cerebrospinal fluid (CSF), urine, saliva, or other bodily fluid (stool, tear fluid, synovial fluid, sputum), breath, e.g., as condensed breath, or an extract or purification therefrom, or dilution thereof.
  • Biological samples also include tissue homogenates, tissue sections and biopsy specimens from a live subject, or taken post-mortem.
  • the samples can be prepared, for example where appropriate diluted or concentrated, and stored in the usual manner. It will be understood that methods of the disclosure may be performed in vitro.
  • the biological sample is whole blood, blood serum or plasma, such as blood serum.
  • biosensor means anything capable of detecting the presence of the biomarker. Examples of biosensors are described herein. Biosensors according to the disclosure may comprise a ligand or ligands, as described herein, capable of specific binding to the biomarker. Such biosensors are useful in detecting and/or quantifying a peptide of the disclosure.
  • Embodiment 48 provides the method of Embodiment 47, wherein said assaying step comprises contacting said sample with one or more biosensors capable of detecting the presence or said one or more biomarkers.
  • the biomarker may be directly detected, e.g., by SELDI or MALDI-TOF.
  • the biomarker may be detected directly or indirectly via interaction with a ligand or ligands such as an antibody or a biomarker-binding fragment thereof, or other peptide, or ligand, e.g., aptamer, or oligonucleotide, capable of specifically binding the biomarker.
  • the ligand may possess a detectable label, such as a luminescent, fluorescent or radioactive label, and/or an affinity tag.
  • detecting and/or quantifying can be performed by one or more method(s) selected from the group consisting of: SELDI (-TOF), MALDI (-TOF), a 1-D gel-based analysis, a 2-D gel-based analysis, Mass spec (MS), reverse phase (RP) LC, size permeation (gel filtration), ion exchange, affinity, HPLC, UPLC and other LC or LC MS-based techniques.
  • SELDI SELDI
  • MALDI MALDI
  • MS mass spec
  • RP reverse phase
  • size permeation gel filtration
  • ion exchange affinity
  • HPLC HPLC
  • UPLC UPLC
  • LC MS-based techniques include ICAT ® (Applied Biosystems, CA, USA), or iTRAQ ® (Applied Biosystems, CA, USA).
  • Methods according to the disclosure may comprise analyzing a sample of blood serum by SELDI-TOF or MALDI-TOF to detect the presence or level of the biomarker. These methods are also suitable for clinical screening, prognosis, monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, for drug screening and development, and identification of new targets for drug treatment.
  • Detecting and/or quantifying the biomarkers may be performed using an immunological method, involving an antibody, or a fragment thereof capable of specific binding to the biomarker.
  • Suitable immunological methods include sandwich immunoassays, such as sandwich ELISA, in which the detection of the biomarkers is performed using two antibodies which recognize different epitopes on a biomarker; radioimmunoassays (RIA), direct, indirect or competitive enzyme linked immunosorbent assays (ELISA), enzyme immunoassays (EIA), Fluorescence immunoassays (FIA), western blotting, immunoprecipitation and any particle- based immunoassay (e.g., using gold, silver, or latex particles, magnetic particles, or Q-dots).
  • I mmunological methods may be performed, for example, in microtitre plate or strip format.
  • I mmunological methods in accordance with the disclosure may be based, for example, on any of the following methods.
  • I mmunoprecipitation is the simplest immunoassay method; this measures the quantity of precipitate, which forms after the reagent antibody has incubated with the sample and reacted with the target antigen present therein to form an insoluble aggregate. I mmunoprecipitation reactions may be qualitative or quantitative.
  • I n particle immunoassays several antibodies are linked to the particle, and the particle is able to bind many antigen molecules simultaneously. This greatly accelerates the speed of the visible reaction. This allows rapid and sensitive detection of the biomarker.
  • Radioimmunoassay (RIA) methods employ radioactive isotopes such as 1125 to label either the antigen or antibody. The isotope used emits gamma rays, which are usually measured following removal of unbound (free) radiolabel.
  • RIA compared with other immunoassays, are higher sensitivity, easy signal detection, and well- established, rapid assays.
  • the major disadvantages are the health and safety risks posed by the use of radiation and the time and expense associated with maintaining a licensed radiation safety and disposal program. For this reason, RIA has been largely replaced in routine clinical laboratory practice by enzyme immunoassays.
  • Enzyme (EIA) immunoassays were developed as an alternative to radioimmunoassays (RIA). These methods use an enzyme to label either the antibody or target antigen. The sensitivity of EIA approaches that of RIA, without the danger posed by radioactive isotopes.
  • EIA enzyme-linked immunosorbent assay
  • ELISA enzyme-linked immunosorbent assay
  • Fluorescent immunoassay refers to immunoassays which utilize a fluorescent label or an enzyme label which acts on the substrate to form a fluorescent product. Fluorescent measurements are inherently more sensitive than colorimetric (spectrophotometric) measurements. Therefore, FIA methods have greater analytical sensitivity than EIA methods, which employ absorbance (optical density) measurement.
  • Chemiluminescent immunoassays utilize a chemiluminescent label, which produces light when excited by chemical energy; the emissions are measured using a light detector.
  • I mmunological methods according to the disclosure ca n thus be performed using well-known methods. Any direct (e.g., using a sensor chip) or indirect procedure may be used in the detection of the biomarker of the disclosure.
  • Biotin-Avidin or Biotin-Streptavidin systems are generic labelling systems that can be adapted for use in immunological methods of the disclosure.
  • One binding partner hapten, antigen, ligand, aptamer, antibody, enzyme etc
  • biotin is labelled with avidin or streptavidin.
  • surface e.g., well, bead, sensor etc
  • avidin or streptavidin is labelled with avidin or streptavidin.
  • a biotinylated ligand e.g., antibody or aptamer
  • a biomarker of the disclosure may be immobilized on an avidin or streptavidin surface, the immobilized ligand may then be exposed to a sample containing or suspected of containing the biomarker in order to detect and/or quantify a biomarker of the disclosure. Detection and/or quantification of the immobilized antigen may then be performed by an immunological method as described herein.
  • antibody as used herein includes, but is not limited to: polyclonal, monoclonal, bispecific, humanized or chimeric antibodies, single chain antibodies, Fab fragments and F(ab')2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies and epitope-binding fragments of any of the above.
  • antibody as used herein also refers to immunoglobulin molecules and immunologically-active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen.
  • the immunoglobulin molecules of the disclosure ca n be of any class (e.g., IgG, IgE, IgM, IgD and IgA) or subclass of immunoglobulin molecule.
  • biosensors can be developed, accordingly, in methods and uses of the disclosure, detecting and quantifying can be performed using a biosensor, microanalytical system, microengineered system, microseparation system, immunochromatography system or other suitable analytical devices.
  • the biosensor may incorporate an immunological method for detection of the biomarker, electrical, thermal, magnetic, optical (e.g., hologram) or acoustic technologies. Using such biosensors, it is possible to detect the target biomarker at the anticipated concentrations found in biological samples.
  • an apparatus for diagnosing or monitoring BPD, SCZ, SAD and/or PRD which comprises a biosensor, microanalytical, microengineered, microseparation and/or immunochromatography system configured to detect and/or quantify the biomarker defined herein.
  • biomarkers of the disclosure can be detected using a biosensor incorporating technologies based on "smart” holograms, or high frequency acoustic systems, such systems are particularly amenable to "bar code” or array configurations.
  • I n smart hologram sensors Smart Holograms Ltd, Cambridge, UK
  • a holographic image is stored in a thin polymer film that is sensitized to react specifically with the biomarker.
  • the biomarker reacts with the polymer leading to an alteration in the image displayed by the hologram.
  • the test result read-out can be a change in the optical brightness, image, color and/or position of the image.
  • a sensor hologram can be read by eye, thus removing the need for detection equipment.
  • a simple color sensor can be used to read the signal when quantitative measurements are required. Opacity or color of the sa mple does not interfere with operation of the sensor.
  • the format of the sensor allows multiplexing for simultaneous detection of several substances. Reversible and irreversible sensors can be designed to meet different requirements, and continuous monitoring of a particular biomarker of interest is feasible.
  • Biosensors for detection of biomarkers of the disclosure may in some embodiments combine biomolecular recognition with appropriate means to convert detection of the presence, or quantitation, of the biomarker in the sample into a signal.
  • Biosensors can be adapted for "alternate site” diagnostic testing, e.g., in the ward, outpatients' department, surgery, home, field and workplace.
  • Biosensors to detect the biomarker of the disclosure include acoustic, plasmon resonance, holographic and microengineered sensors. Imprinted recognition elements, thin film transistor technology, magnetic acoustic resonator devices and other novel acousto- electrical systems may be employed in biosensors for detection of the bioma rker of the disclosure.
  • Methods involving detection and/or quantification of the biomarker of the disclosure can be performed on bench-top instruments, or ca n be incorporated onto disposable, diagnostic or monitoring platforms that can be used in a non-laboratory environment, e.g., in the physician's office or at the patient's bedside.
  • Suitable biosensors for performing methods of the disclosure include "credit" cards with optical or acoustic readers.
  • Biosensors ca n be configured to allow the data collected to be electronically transmitted to the physician for interpretation and thus can form the basis for e-neuromedicine.
  • Any suitable animal may be used as a subject non-human animal, for example a non-human primate, horse, cow, pig, goat, sheep, dog, cat, fish, rodent, e.g., guinea pig, rat or mouse; insect (e.g., Drosophila), amphibian (e.g., Xenopus) or C. elegans.
  • a non-human primate horse, cow, pig, goat, sheep, dog, cat, fish
  • rodent e.g., guinea pig, rat or mouse
  • insect e.g., Drosophila
  • amphibian e.g., Xenopus
  • C. elegans C. elegans.
  • a method of identifying a substance capable of promoting or suppressing the generation of the biomarker in a subject comprising exposing a test cell to a test substance and monitoring the level of the biomarker within said test cell, or secreted by said test cell.
  • the test cell could be prokaryotic or, in some embodiments, a eukaryotic cell may be employed in cell-based testing methods.
  • the eukaryotic cell is a yeast cell, insect cell, Drosophila cell, amphibian cell (e.g., from Xenopus), C. elegans cell or is a cell of human, non-human primate, equine, bovine, porcine, caprine, ovine, canine, feline, piscine, rodent or murine origin.
  • the test substance can be a known chemical or pharmaceutical substance, such as, but not limited to, an anti-psychotic disorder therapeutic; or the test substance can be novel synthetic or natural chemical entity, or a combination of two or more of the aforesaid substances.
  • I n methods for identifying substances of potential therapeutic use non-human animals or cells can be used that are capable of expressing the peptide.
  • Screening methods also encompass a method of identifying a ligand capable of binding to the biomarker according to the disclosure, comprising incubating a test substance in the presence of the biomarker in conditions appropriate for binding, and detecting and/or quantifying binding of the peptide to said test substance.
  • High-throughput screening technologies based on the biomarker uses and methods of the disclosure, e.g., configured in an array format, are suitable to monitor biomarker signatures for the identification of potentially useful therapeutic compounds, e.g., ligands such as natural compounds, synthetic chemical compounds (e.g., from combinatorial libraries), peptides, monoclonal or polyclonal antibodies or fragments thereof, which may be capable of binding the biomarker.
  • the disclosure further provides a substance, e.g., a ligand, identified or identifiable by an identification or screening method or use of the disclosure.
  • a substance e.g., a ligand, identified or identifiable by an identification or screening method or use of the disclosure.
  • Such substances may be capable of inhibiting, directly or indirectly, the activity of the biomarker, or of suppressing generation of the biomarker.
  • the term "substances" includes substances that do not directly bind the biomarker and directly modulate a function, but instead indirectly modulate a function of the biomarker.
  • Ligands are also included in the term substances; ligands of the disclosure (e.g., a natural or synthetic chemical compound, peptide, aptamer, oligonucleotide, antibody or antibody fragment) are capable of binding, suitably specific binding, to the peptide.
  • the disclosure further provides a substance according to the disclosure for use in the treatment of schizophrenia, or predisposition thereto.
  • kits for diagnosing, prognosing and/or monitoring schizophrenia comprising reagents and/or a biosensor capable of detecting and/or quantifying the biomarkers described herein.
  • a kit according to the disclosure may contain one or more components selected from the group: a ligand specific for the biomarker or a structural/shape mimic of the biomarker, one or more controls, one or more reagents and one or more consumables; optionally together with instructions for use of the kit in accordance with any of the methods defined herein.
  • kits for the diagnosis, prognosis and monitoring of schizophrenia or other psychotic disorder are described herein. I n one embodiment, the kits additionally contain a biosensor capable of detecting and/or quantifying a biomarker.
  • the identification of biomarkers for schizophrenia or other psychotic disorder permits integration of diagnostic procedures and therapeutic regimes. Currently there are significant delays in determining effective treatment and hitherto it has not been possible to perform rapid assessment of drug response. Traditionally, many anti-psychotic therapies have required treatment trials lasting weeks to months for a given therapeutic approach. Detection of a biomarker of the disclosure can be used to screen subjects prior to their participation in clinical trials.
  • the biomarkers provide the means to indicate therapeutic response, failure to respond, unfavorable side-effect profile, degree of medication compliance and achievement of adequate serum drug levels.
  • the biomarkers may be used to provide warning of adverse drug response. Therefore, future application of this test could aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention.
  • Biomarkers are useful in development of personalized brain therapies, as assessment of response ca n be used to fine-tune dosage, minimize the number of prescribed medications, reduce the delay in attaining effective therapy and avoid adverse drug reactions.
  • patient care can be tailored precisely to match the needs determined by the disorder and the pharmacogenomic profile of the patient, the biomarker can thus be used to titrate the optimal dose, predict a positive therapeutic response and identify those patients at high risk of severe side effects.
  • Biomarker-based tests provide a first line assessment of 'new' patients, and provide objective measures for accurate and rapid diagnosis, in a time frame and with precision, not achievable using the current subjective measures.
  • diagnostic biomarker tests are useful to identify family members or patients at high risk of developing schizophrenia or other psychotic disorder. This permits initiation of appropriate therapy, or preventive measures, e.g., managing risk factors. These approaches are recognized to improve outcome and may prevent overt onset of the disorder.
  • Biomarker monitoring methods, biosensors and kits are also vital as patient monitoring tools, to enable the physician to determine whether relapse is due to worsening of the disorder, poor patient compliance or substance abuse. If pharmacological treatment is assessed to be inadequate, then therapy can be reinstated or increased; a change in therapy can be given if appropriate. As the biomarker is sensitive to the state of the disorder, it provides an indication of the impact of drug therapy or of substance abuse.
  • results of any analyses according to the disclosure will often be communicated to physicians and/or patients (or other interested parties such as researchers) in a transmittable form that can be communicated or transmitted to any of the above parties.
  • a form can vary and can be tangible or intangible.
  • the results can be embodied in descriptive statements, diagrams, photographs, charts, images or any other visual forms.
  • the statements and visual forms can be recorded on a tangible medium such as papers, computer readable media such as hard disks, compact disks, etc., or on an intangible medium, e.g., an electronic medium in the form of email or website on internet or intranet.
  • results can also be recorded in a sound form and transmitted through any suitable medium, e.g., analog or digital cable lines, fiber optic cables, etc., via telephone, facsimile, wireless mobile phone, internet phone and the like.
  • the information and data on a test result can be produced anywhere in the world and transmitted to a different location.
  • the information and data on a test result may be generated, cast in a transmittable form as described above, and then imported into the United States.
  • the present disclosure also encompasses a method for producing a transmittable form of information on levels of one or more analyte biomarkers or levels of a specific panel of analyte biomarkers for at least one patient sample.
  • the method comprises the steps of (1) determining levels of one or more analyte biomarkers or levels of a specific panel of analyte biomarkers for at least one patient sample according to methods of the present disclosure; and (2) embodying the result of the determining step in a transmittable form.
  • the transmittable form is the product of such a method.
  • the present disclosure further provides a system for determining whether an individual suffers from schizophrenia, comprising: (1) a sample analyzer for determining the levels of one or more analyte biomarkers or levels of a specific panel of analyte biomarkers for at least one patient sample, wherein the sample analyzer contains the patient sample; (2) a first computer program for (a) receiving data regarding the levels of one or more analyte biomarkers or the levels of a specific panel of analyte biomarkers; and optionally (3) a second computer program for comparing the test value to one or more reference standards each associated with a predetermined degree of risk of schizophrenia.
  • the sample analyzer can be any instruments useful in determining the levels of biomarkers in a sample, as described herein.
  • the computer-based analysis function can be implemented in any suitable language and/or browsers. For example, it may be implemented with C language and preferably using object-oriented high-level programming languages such as Visual Basic, SmallTalk, C++, and the like.
  • the application can be written to suit environments such as the Microsoft WindowsTM environment including WindowsTM 98, WindowsTM 2000, WindowsTM NT, and the like. I n addition, the application ca n also be written for the Macl ntoshTM, SUNTM, UNIX or LIN UX environment.
  • the functional steps can also be implemented using a universal or platform-independent programming language.
  • multi-platform programming languages include, but are not limited to, hypertext markup language (HTML), JAVATM, JavaScriptTM, Flash programming language, common gateway interface/structured query language (CGI/SQL), practical extraction report language (PERL), AppleScriptTM and other system script languages, programming language/structured query language (PL/SQL), and the like.
  • JavaTM- or JavaScriptTM-enabled browsers such as HotJavaTM, MicrosoftTM ExplorerTM, or NetscapeTM can be used.
  • active content web pages may include JavaTM applets or ActiveXTM controls or other active content technologies.
  • the analysis function can also be embodied in computer program products and used in the systems described above or other computer- or internet-based systems.
  • a computer program product comprising a computer-usable medium having computer-readable program codes or instructions embodied thereon for enabling a processor to carry out disease risk analysis.
  • These computer program instructions may be loaded onto a computer or other programmable apparatus to produce a machine, such that the instructions which execute on the computer or other programmable apparatus create means for implementing the functions or steps described above.
  • These computer program instructions may also be stored in a computer- readable memory or medium that can direct a computer or other programmable apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory or medium produce an article of manufacture including instructions which implement the analysis.
  • the computer program instructions may also be loaded onto a computer or other programmable apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions or steps described above.
  • the system comprises (1) computer program for receiving, storing, and/or retrieving data regarding levels of biomarkers in a patient's sample and optionally clinical parameter data (e.g., disease-related symptoms); (2) computer program for querying this patient data; (3) computer program for concluding whether an individual suffers from schizophrenia based on this patient data; and optionally (4) computer program for outputting/displaying this conclusion.
  • this computer program for outputting the conclusion may comprise a computer program for informing a health care professional of the conclusion.
  • Computer software products of the disclosure typically include computer readable media having computer-executable Instructions for performing the logic steps of the method of the disclosure.
  • Suitable computer readable medium include floppy disk, CD-ROM/DVD/DVD-ROM, hard-disk drive, flash memory, ROM/RAM, magnetic tapes and etc.
  • Basic computational biology methods are described in, for example, Setubal et al., INTRODUCTION TO COMPUTATIONAL BIOLOGY METHODS (PWS Publishing Company, Boston, 1997); Salzberg et al.
  • BIOINFORMATICS BASICS APPLICATION IN BIOLOGICAL SCIENCE AND MEDICINE (CRC Press, London, 2000); and Ouelette & Bzevanis, Attorney Docket No. 3330-01-lP Page 38 of 64 BIOINFORMATICS: A PRACTICAL GUIDE FOR ANALYSIS OF GENE AND PROTEINS (Wiley & Sons, Inc., 2nd ed., 2001); see also, U.S. Pat. No. 6,420,108.
  • BMI Body mass index
  • a weighted scoring approach based on a set of pair-wise two-way/binomial classification models was particularly accurate in classifying disease states.
  • the 7 pairwise models would be 1) Controls vs Disease, 2) Controls vs BPD, 3) Controls vs SCZ, 4) Controls vs SAD, 5) BPD vs SCZ, 6) BPD, vs SAD, and 7) SCZ vs SAD.
  • Lasso regression provided results that were confirmatory to the LDA/CDA findings.
  • the 7 pairwise models in Study 2 consisted of 7 to 19 analytes, with their Average Cross-validation AUCs ranging from 0.57 to 0.88 (see Figure 7).
  • Lasso regression and LDA can be used to develop a set of models (each with 10-12 analytes), that can be used as the basis of a weighted scoring algorithm to effectively classify new subjects.

Abstract

La présente invention concerne des biomarqueurs et des méthodes destinées à diagnostiquer ou à surveiller un trouble bipolaire, la schizophrénie, un trouble schizo-affectif et le syndrome prodromique, ou une prédisposition à ceux-ci.
PCT/US2016/023915 2015-03-27 2016-03-24 Nouveaux biomarqueurs pour troubles psychiatriques WO2016160484A1 (fr)

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