Proteomic risk scoring for osteoarthritis (OA)

Abstract

Presented herein are methods of determining the risk of a subject to develop OA and / or progression to total joint replacement (TJR) and determining the therapeutic response of the subject to an NGF antagonist or NSAID treatment by determining an osteoarthritis (OA) proteomic risk score for the subject.

Description

Technical Field

[0001] The present disclosure relates to methods for determining a subject's risk of developing osteoarthritis (OA) and / or progressing to total joint replacement (TJR) and determining a subject's response to treatment with a nerve growth factor (NGF) antagonist or a nonsteroidal anti-inflammatory drug (NSAID) by determining a subject's osteoarthritis (OA) proteomic risk score. Background Art

[0002] Proteomic risk scores combine information on protein expression or circulating levels of many proteins derived from disease association studies to create a single quantitative measure for each individual. Proteomic risk scores are typically constructed as a weighted sum of the expression or circulating levels of a selected set of proteins from subjects with a specific disease compared to a reference population. The resulting score is approximately normally distributed in the general population, with higher scores indicating greater risk or disease and / or need for specific treatment options. As the availability of proteomic data from large cohort studies increases, the incorporation of proteomic risk scores is likely to become more common. Historically, this required specialized expertise, but with the improvement of tools and data availability, calculating scores for analysis is becoming more feasible.

[0003] Osteoarthritis is the most common form of arthritis, affecting an estimated 303 million people worldwide in 2017, with pain being the primary symptom associated with the disease. OA is a degenerative disease of the synovial joints, including the knees, hips, facet joints of the spine, and hands. Risk factors for OA include aging, previous joint injury, obesity, female gender, and genetics. These risk factors are associated with the underlying pathogenesis of OA, a complex process influenced by altered biomechanics, chronic low-level inflammation, and aging. All of these processes can promote degeneration and remodeling of joint tissues, which ultimately leads to a loss of the structural integrity of the joint. While these joint diseases and arthritis do not directly lead to death, they can cause pain and limb dysfunction due to the progressive destruction of cartilage and bone over time, significantly impacting daily life.

[0004] R475-OA-1688 is a Phase 3, randomized, double-blind, multiple-dose, placebo- and NSAID-controlled study designed to evaluate the efficacy and safety of Faskinumab in patients with painful osteoarthritis of the knee or hip. The primary efficacy objective of R475-OA-1688 is to evaluate the change from baseline to Week 24 in the Western Ontario and McMaster Universities Osteoarthritis Scale (WOMAC) pain subscale and function subscale in patients treated with Faskinumab compared with patients treated with NSAIDs or placebo. The primary safety objective of R475-OA-1688 is to determine the incidence of total joint replacement during treatment and follow-up. Summary of the Invention

[0005] The present disclosure provides a method for determining a subject's risk of developing OA, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; wherein: when the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's risk of developing OA is increased; and when the subject's osteoarthritis proteomic risk score is less than the threshold osteoarthritis proteomic risk score, the subject's risk of developing OA is decreased.

[0006] The present disclosure also provides a method for determining a subject's risk of progressing to total joint replacement (TJR), the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; wherein: when the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's risk of progressing to TJR is increased; and when the subject's osteoarthritis proteomic risk score is less than the threshold osteoarthritis proteomic risk score, the subject's risk of progressing to TJR is decreased.

[0007] The present disclosure also provides a method for determining a therapeutic response in a subject treated with an NGF antagonist, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of the expression levels or circulating levels of one or more proteins associated with OA; wherein: when the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's response to the NGF antagonist is less; and when the subject's osteoarthritis proteomic risk score is less than a threshold osteoarthritis proteomic risk score, the subject's response to the NGF antagonist is increased.

[0008] The present disclosure also provides a method of determining a treatment response in a subject being treated with an NSAID, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; wherein: when the osteoarthritis proteomic risk score for the subject is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's response to the NSAID is diminished; and when the osteoarthritis proteomic risk score for the subject is less than the threshold osteoarthritis proteomic risk score, the subject's response to the NSAID is increased.

[0009] The present disclosure also provides a method for determining a treatment response in a subject, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; wherein: when the osteoarthritis proteomic risk score of the subject is greater than or equal to a threshold osteoarthritis proteomic risk score, the treatment response of the subject is less; and when the osteoarthritis proteomic risk score of the subject is less than the threshold osteoarthritis proteomic risk score, the treatment response of the subject is increased. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] This patent or application file contains at least one drawing drawn in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0011] Figure 1 Shown are the percentages of total joint replacements (Y-axis) in OA patients from the UK Biobank Pharmaceutical Proteomics Project (UKBPPP), stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in quartile.

[0012] Figure 2 Shown are Kaplan-Meier curves for total joint replacement in UK Biobank Pharmaceutical Proteomics Project (UKB PPP) OA patients stratified by proteomic risk score quartiles; quartile 4 had the highest risk, while quartile 1 had the lowest risk.

[0013] Figure 3 Shown are the percentages of total joint replacements for OA patients among all patients in the R475-OA-1688 clinical trial (including all patients treated with faskinumab, NSAIDs, or placebo) stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in the quartile.

[0014] Figure 4Shown are the percentages of total joint replacements in patients with OA treated with all doses of Faskinumab (including all 1q4w, 3q4w, and 6q8w) in the R475-OA-1688 clinical trial (Y-axis), stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in the quartile.

[0015] Figure 5 Shown are the percentages of total joint replacements in patients with OA treated with high-dose fastenumab (including both 3q4w and 6q8w) in the R475-OA-1688 clinical trial (Y-axis), stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in the quartile.

[0016] Figure 6 Shown are the percentages of total joint replacements in patients with OA who were treated with Faskinumab 1q4w in the R475-OA-1688 clinical trial (Y-axis), stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in the quartile.

[0017] Figure 7 Shown are the percentages of total joint replacements for OA patients among NSAID-treated patients in the R475-OA-1688 clinical trial (Y-axis), stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in the quartile.

[0018] Figure 8 Shown are the percentages of total joint replacements for OA patients among placebo-treated patients in the R475-OA-1688 clinical trial (Y-axis), stratified by proteomic risk score quartiles (X-axis); quartile 4 had the highest risk, while quartile 1 had the lowest risk; OR / SD = odds ratio / standard deviation, N samples = number of subjects in the study, N = number of subjects in the quartile.

[0019] Figure 9Figure 3. The least squares mean change in WOMAC pain scores (Y-axis) from baseline over time (X-axis) for all patients treated with Faskinumab 1q4w, NSAIDs, and placebo, stratified by proteomic risk score risk group. The high-risk group was defined by patients in the OAPRS quartile 4, and patients in quartiles 1 to 3 were defined as the low-risk group.

[0020] Figure 10 Figure 3. Least squares mean change in WOMAC functional score (Y-axis) from baseline over time (X-axis) for all patients treated with Faskinumab 1q4w, NSAIDs, and placebo, stratified by proteomic risk score risk group. The high-risk group was defined by patients in the OAPRS quartile 4, and patients in quartiles 1 to 3 were defined as the low-risk group.

[0021] Figure 11 Figure 3. The least squares mean change in WOMAC pain scores (Y-axis) from baseline over time (X-axis) for all patients treated with faskinumab 1q4w, celecoxib, diclofenac, and placebo, stratified by proteomic risk score risk group. The high-risk group was defined by patients in the 4th quartile of the OAPRS, and patients in the 1st to 3rd quartiles were defined as the low-risk group.

[0022] Figure 12 Figure 3. Least squares mean change in WOMAC functional score (Y-axis) from baseline over time (X-axis) for all patients treated with faskinumab 1q4w, celecoxib, diclofenac, and placebo, stratified by proteomic risk score risk group. The high-risk group was defined by patients in the 4th quartile of the OAPRS, and patients in the 1st to 3rd quartiles were defined as the low-risk group. DETAILED DESCRIPTION

[0023] Protein expression levels or circulating levels can play an important role in the risk of developing a disease and potentially affect how such a disease or condition progresses to a more advanced stage requiring a specific treatment. A proteomic risk score combines information on the expression levels or circulating levels of multiple proteins derived from disease association studies to create a single composite quantitative metric for each individual that reflects their disease risk. Combining risk assessments of multiple proteins provides the advantage of increased predictive power. An individual with a large number of relevant protein expression levels or circulating levels for a particular disease will have a higher proteomic risk score than an individual with fewer relevant protein expression levels or circulating levels for the same particular disease. Risk can be evaluated at several thresholds (such as percentiles of a population distribution, standard deviation units, or absolute values). The present disclosure generally relates to the unexpected discovery that stratification of subjects by OA proteomic risk scoring can be used to identify subjects who are likely to develop OA and / or avoid arthropathy side effects of NGF antagonists in the treatment of OA pain, and can also demonstrate differential responses to both NGF antagonist and NSAID treatment.

[0024] Various terms related to aspects of the present disclosure are used throughout the specification and claims. Unless otherwise indicated, such terms are to be given their ordinary meanings in the art. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0025] Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Therefore, in the claims or specification, when a method claim does not specifically state that the steps are limited to a specific order, no order is intended to be inferred in any respect. This applies to any possible non-express basis for interpretation, including matters of logic with respect to the arrangement of steps or operational flow, ordinary meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0026] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0027] As used herein, the term "about" means that the recited numerical values ​​are approximate and that small variations do not significantly affect the practice of the disclosed embodiments. Where numerical values ​​are used, unless the context indicates otherwise, the term "about" means that the numerical value may vary by ±10% and still be within the scope of the disclosed embodiments.

[0028] As used herein, the term "antagonist" means that a given compound is able to inhibit the activity of a corresponding protein or other substance in a cell by at least a certain amount. This can be achieved by direct interaction of the compound with a given protein or substance ("direct inhibition") or by interaction of the compound with other proteins or other substances within or outside the cell (which results in at least partial inhibition of the activity of the protein or substance) ("indirect inhibition"). Inhibition of protein activity can also be achieved by suppressing the expression of the target protein. Technologies for inhibiting protein expression include, but are not limited to, antisense inhibition, siRNA-mediated inhibition, miRNA-mediated inhibition, ribozyme-mediated inhibition, DNA-guided RNA interference (DdRNAi), RNA-guided DNA methylation, transcription activator-like effector nuclease (TALEN)-mediated inhibition, zinc finger nuclease-mediated inhibition, aptamer-mediated inhibition, and CRISPR-mediated inhibition.

[0029] As used herein, the terms "nerve growth factor" and "NGF" refer to nerve growth factor and variants thereof that retain at least a portion of the activity of NGF (including, for example, splice variants and protein processing variants). As used herein, NGF includes all mammalian species of native sequence NGF, including humans, non-human primates, dogs, cats, horses, or cattle.

[0030] "NGF antagonist" refers to any molecule that blocks, inhibits or reduces (including significantly) the biological activity of NGF, including downstream pathways mediated by NGF signaling, such as receptor binding and / or initiation of cellular responses to NGF. The term "antagonist" does not imply any particular biological mechanism of action and is considered to explicitly include and encompass all possible pharmacological, physiological and biochemical interactions with NGF, whether direct or indirect, whether with NGF, its receptor, or through another mechanism, and the results that can be achieved by a variety of different and chemically distinct compositions. Exemplary NGF antagonists include, but are not limited to, anti-NGF antibodies, antisense molecules directed against NGF (including antisense molecules directed against nucleic acids encoding NGF), NGF antagonist compounds, NGF structural analogs, dominant negative mutations of the TrkA receptor that binds NGF, TrkA immunoadhesins, anti-TrkA antibodies, anti-p75 antibodies, antisense molecules directed against either or both of the TrkA and / or p75 receptors (including antisense molecules directed against nucleic acid molecules encoding TrkA or p75), and kinase inhibitors. For the purposes of this disclosure, it will be understood that the term "antagonist" encompasses all previously identified terms, titles, and functional states and characteristics whereby NGF itself, NGF biological activity (including but not limited to its ability to mediate any aspect of pain), or the results of the biological activity are substantially ineffective, reduced, or neutralized to any meaningful extent. In some embodiments, an NGF antagonist binds to NGF (e.g., an antibody) (physically interacts with NGF), binds to an NGF receptor (such as a trkA receptor or a p75 receptor), reduces (hinders and / or blocks) downstream NGF receptor signaling, and / or inhibits (reduces) NGF synthesis, production, or release. In some embodiments, an NGF antagonist binds to NGF (e.g., an antibody) (physically interacts with NGF), binds to an NGF receptor (such as a TrkA receptor or a p75 receptor), and / or reduces (hinders and / or blocks) downstream NGF receptor signaling. In other embodiments, an NGF antagonist binds to NGF and prevents TrkA receptor dimerization and / or TrkA autophosphorylation. In other embodiments, an NGF antagonist inhibits or reduces NGF synthesis and / or production (release). Examples of types of NGF antagonists are provided herein.

[0031] As used herein, the term "NSAID" refers to any nonsteroidal anti-inflammatory drug, including but not limited to any NSAID disclosed herein.

[0032] As used herein, "prophylactic treatment" and "prevention" refer to administration to a subject who currently has or has never had OA.

[0033] As used herein, the term "subject" includes any animal, including mammals. Mammals include, but are not limited to, farm animals (e.g., horses, cows, pigs), companion animals (e.g., dogs, cats), laboratory animals (e.g., mice, rats, rabbits), and non-human primates (e.g., apes and monkeys). In some embodiments, the subject is a human. In some embodiments, the subject is a patient under the care of a physician.

[0034] As used herein, "therapeutic treatment" refers to the administration of a therapeutic agent to a subject suffering from OA.

[0035] As used herein, the terms "treat," "treatment," or "treating" refer to the administration of a therapeutic agent for prophylactic and / or therapeutic purposes.

[0036] The present disclosure provides a method for determining the risk of a subject developing osteoarthritis (OA). The method includes determining or having determined an osteoarthritis proteomic risk score for a subject, wherein the osteoarthritis proteomic risk score includes a weighted sum of expression levels or circulating levels of one or more proteins associated with OA. When the osteoarthritis proteomic risk score of the subject is greater than or equal to a threshold osteoarthritis proteomic risk score, the risk of the subject developing OA increases. When the osteoarthritis proteomic risk score of the subject is less than a threshold osteoarthritis proteomic risk score, the risk of the subject developing OA decreases.

[0037] The present disclosure also provides a method for determining the risk of a subject progressing to total joint replacement (TJR). The method includes determining or having determined an osteoarthritis proteomic risk score for a subject, wherein the osteoarthritis proteomic risk score includes a weighted sum of the expression levels or circulating levels of one or more proteins associated with OA. When the osteoarthritis proteomic risk score of the subject is greater than or equal to a threshold osteoarthritis proteomic risk score, the risk of the subject progressing to TJR increases. When the osteoarthritis proteomic risk score of the subject is less than a threshold osteoarthritis proteomic risk score, the risk of the subject progressing to TJR decreases.

[0038] The present disclosure also provides a method for determining a therapeutic response in a subject treated with an NGF antagonist, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of the expression levels or circulating levels of one or more proteins associated with OA; wherein: when the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's response to the NGF antagonist is less; and when the subject's osteoarthritis proteomic risk score is less than a threshold osteoarthritis proteomic risk score, the subject's response to the NGF antagonist is increased.

[0039] The present disclosure also provides a method of determining a treatment response in a subject being treated with an NSAID, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; wherein: when the osteoarthritis proteomic risk score for the subject is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's response to the NSAID is diminished; and when the osteoarthritis proteomic risk score for the subject is less than the threshold osteoarthritis proteomic risk score, the subject's response to the NSAID is increased.

[0040] The present disclosure also provides a method for determining a treatment response in a subject, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; wherein: when the osteoarthritis proteomic risk score of the subject is greater than or equal to a threshold osteoarthritis proteomic risk score, the treatment response of the subject is less; and when the osteoarthritis proteomic risk score of the subject is less than the threshold osteoarthritis proteomic risk score, the treatment response of the subject is increased.

[0041] In some embodiments, the subject may have had OA within the past 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months. In some embodiments, the subject may have had OA within the past 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years. The subject may include subjects who have been hospitalized with symptoms associated with OA and subjects who are currently hospitalized.

[0042] The osteoarthritis proteomic risk score comprises a weighted sum of the expression levels or circulating levels of one or more proteins associated with OA. The number of proteins associated with OA can be 1 protein, at least about 2 proteins, at least about 5 proteins, at least about 10 proteins, at least about 15 proteins, at least about 20 proteins, at least about 30 proteins, at least about 40 proteins, at least about 50 proteins, at least about 100 proteins, or at least about 200 proteins.

[0043] Table 1 shows the protein-wide association analysis with OA discovery data for the top 199 proteins that were statistically significant after Bonferroni correction (p-value cutoff: 1.7e-5).

[0044] Table 1: Summary of OA proteome-wide association analysis

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] In some embodiments, the one or more proteins associated with OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acidic protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrix protein-3 (MATN3), cartilage oligomeric matrix protein (COMP), CUB domain-containing protein 1 (CDCP1), protein BRICK1 (BRK1), gastrin (GAST), collagen Protein alpha-3 (VI) chain (COL6A3), protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), fibroblast growth factor binding protein 2 (FGFBP2), annexin A10 (ANXA10), chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), osteopontin (SPP1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor binding protein 4 (IGFBP4), heart-type fatty acid binding protein (FABP3), triggering protein expressed on myeloid cells receptor 2 (TREM2), transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-associated protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGRG2), myosin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), slow-type myosin binding protein C (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), mitochondrial protein containing coiled-coil domain 10 (CHCHD10), myosin light chain 3 (MYL3), macrophage Metalloelastase (MMP12), hepatitis A virus cellular receptor 2 (HAVCR2), lamin B2 (LMNB2), trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocan core protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b binding protein β chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase 3-like protein 1 (CHI3L1), protein kinase C binding protein NELL2 (NELL2), contact protein 1 (CNTN1), cytoplasmic branched-chain amino acid aminotransferase (BCAT1),Transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor binding protein 1 (IGFBP1), secretin (SCT), collagen lectin 12 (COLEC12), prolargin (PRELP), alpha-actinin 2 (ACTN2), tight junction Adapter protein (OCLN), galectin 3 (LGALS3), cathepsin L1 (CTSL), dipeptidyl aminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyrotropin subunit β (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin 2 (CNTN2), persephin (PSPN), arginase 1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor binding protein 2 (IGFBP2), anterior gradient protein 2 homolog (AGR2) , trefoil factor 2 (TFF2), neural cell adhesion molecule (NRCAM), sushi domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), chelonasin homolog A (IGSF9), tenascin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphokinase 1 (TPK1), UL16 binding protein 2 (ULBP2), hypoxia upregulated protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), exo-ADP ribosyltransferase 3 (ART3), protein kinase C binding protein NELL1 (NELL 1), macrophage scavenger receptor type I and II (MSR1), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cellular receptor 1 (HAVCR1), peroxidase 2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuronal protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin B subunit type 1 (PPP3R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), brevican core protein (BCAN),Cerebellar peptide 4 (CBLN4), creatine kinase type B (CKB), a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), connexin 2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), uncharacterized protein C9orf40 (C9orf40), protein DDI1 homolog 2 (DDI2), stromelysin 1 (MMP3), adiponectin (ADIPOQ), CMP-N-acetylneuraminic acid-β-galactosamide-α-2,3-sialyltransferase 1 (ST3GAL1), Layilin (LAYN), porphobilinogen dehydrogenase (HMBS), tumor necrosis factor receptor superfamily member 3 (LTBR), lysosomal Pro- X carboxypeptidase (PRCP), centromere protein F (CENPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myenterin 2 (MYOM2), receptor tyrosine-protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin 4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor responsive protein 2 (RARRES2), CC motif chemokine 7 (CCL7), stanniocalcin 1 (STC1), osteocalcin (BGLAP), interleukin 15 (IL15), protein-glutamine gamma-glutamyltransferase 2 (TGM2), latent transforming growth factor beta-binding protein 2 (LTBP2), interferon-gamma-induced lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal-type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 (EPHB4), dystrophin beta (DTNB) , neutrophil cytoplasmic factor 2 (NCF2), Mimecan (OGN), alpha hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), Tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enabled homolog (ENAH), galectin 1 (LGALS1), mitochondrial hydroxyacylglutathione hydrolase (HAGH), fetuin B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), C-type lectin domain family 5 member A (CLEC5A),A disintegrin and metalloproteinase with thrombospondin motif 13 (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family chaperone regulatory protein 3 (BAG3), sclerostin (SOST), Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain-containing protein 80 (CCDC80), odontogenic ameloblast-associated protein (ODAM), cystatin B (CSTB), seizure 6-like protein (SEZ6L), stanniocalcin 2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-associated protein 8 (MXRA8), macrophages. phagocyte capping protein (CAPG), band 3 anion transporter (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (NPPC), cystatin D (CST5), low-density lipoprotein receptor-related protein 1 (LRP1), CC motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1-glycoprotein 1 (PSG1), gastric opsonin (FABP6), ephrin A1 (EFNA1), thrombomodulin (THBD), DnaJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerylphosphocholine choline phosphodiesterase ENPP6 (ENPP6) or parathyroid hormone (PTH), or any combination thereof comprising at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 proteins. In some embodiments, the one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH and / or BRK1, or any combination thereof.

[0052] The expression level or circulating level of any one or more of these proteins can be determined by any method for determining protein expression level or circulating level. In some embodiments, protein expression level or circulating level is determined by proximity extension assay using oligonucleotide coupled antibody pairs, which are measured by sequencing (see Sun et al., 2022). Other methods include high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC / MS), enzyme-linked immunosorbent assay (ELISA), protein immunoprecipitation, immunoelectrophoresis, western blotting, and protein immunostaining. High-throughput proteomics includes protein pathway arrays, next-generation tissue microarrays, single-cell proteomics, single-molecule proteomics, suspension bead array technology (Luminex), multiplex bead assays (Simoa), nanoparticle (Seer) and proximity extension assay (Olink) proteomics, and aptamer-based multiplex proteomics (Somalogic) (see, for example, Cui et al., Lab. Invest., 2022, 102, 1170-1181; and Suhre et al., Nat. Rev. Genet., 2021, 22, 19-37).

[0053] In some embodiments, the osteoarthritis proteomic risk score is determined by the following formula: (0.76×COL9A1 protein level)+(0.67×CRTAC1 protein level)+(−0.26×CNTN1 protein level)+(0.08×GAST protein level)+(−0.45×CYTL1 protein level)+(0.13×KLK4 protein level)+(−0.19×DLK1 protein level)+(0.15×CDCP1 protein level)+(−0.19×DPP10 protein level)+(−0.19×CELA2 A protein level) + (0.22 × RBFOX3 protein level) + (0.18 × CRELD1 protein level) + (-0.23 × NELL2 protein level) + (0.10 × PGA4 protein level) + (-0.10 × ARG1 protein level) + (-0.25 × ART3 protein level) + (0.14 × TIMD4 protein level) + (0.15 × FGFBP2 protein level) + (-0.06 × BPIFA2 protein level) + (-0.08 × PTH protein level) + (0.12 × BRK1 protein level).

[0054] In some embodiments, the osteoarthritis proteomic risk score is determined by the following formula: (about 0.76×COL9A1 protein level) + (about 0.67×CRTAC1 protein level) + (about −0.26×CNTN1 protein level) + (about 0.08×GAST protein level) + (about −0.45×CYTL1 protein level) + (about 0.13×KLK4 protein level) + (about −0.19×DLK1 protein level) + (about 0.15×CDCP1 protein level) + (about −0.19×DPP10 protein level) + (about −0.19×CELA2A protein level) protein level) + (about 0.22 × RBFOX3 protein level) + (about 0.18 × CRELD1 protein level) + (about -0.23 × NELL2 protein level) + (about 0.10 × PGA4 protein level) + (about -0.10 × ARG1 protein level) + (about -0.25 × ART3 protein level) + (about 0.14 × TIMD4 protein level) + (about 0.15 × FGFBP2 protein level) + (about -0.06 × BPIFA2 protein level) + (about -0.08 × PTH protein level) + (about 0.12 × BRK1 protein level).

[0055] In some embodiments, the osteoarthritis proteomic risk score is determined by the following formula: (about 0.8×COL9A1 protein level) + (about 0.7×CRTAC1 protein level) + (about −0.3×CNTN1 protein level) + (about 0.1×GAST protein level) + (about −0.4×CYTL1 protein level) + (about 0.1×KLK4 protein level) + (about −0.2×DLK1 protein level) + (about 0.1×CDCP1 protein level) + (about −0.2×DPP10 protein level) + (about −0.2×CELA2 A protein level) + (about 0.2×RBFOX3 protein level) + (about 0.2×CRELD1 protein level) + (about -0.2×NELL2 protein level) + (about 0.1×PGA4 protein level) + (about -0.1×ARG1 protein level) + (about -0.2×ART3 protein level) + (about 0.1×TIMD4 protein level) + (about 0.2×FGFBP2 protein level) + (about -0.1×BPIFA2 protein level) + (about -0.1×PTH protein level) + (about 0.1×BRK1 protein level).

[0056] The osteoarthritis proteomic risk score is determined based on a biological sample obtained from a subject. In some embodiments, the methods described herein further include an initial step of obtaining a biological sample from a subject. The biological sample may contain intact cells, living cells, and / or cell fragments. The biological sample may contain (or be derived from) a "body fluid." The present disclosure encompasses embodiments in which body fluids are selected from amniotic fluid, aqueous humor, vitreous humor, bile, blood, serum, plasma, breast milk, cerebrospinal fluid, cerumen (earwax), chyle, chyme, endolymph, perilymph, exudate, feces, female semen, gastric acid, gastric juice, lymph, mucus (including nasal drainage and sputum), pericardial fluid, peritoneal fluid, pleural fluid, pus, mucosal secretions, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vomitus, and a mixture of one or more thereof. The biological sample includes cell cultures, body fluids, and cell cultures from body fluids. Body fluids can be obtained from a mammalian organism, for example, by venipuncture or other collection or sampling procedures. In some embodiments, the biological sample comprises blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, cheek swab, or cells.

[0057] In some embodiments, a threshold osteoarthritis proteomic risk score is generated by a reference population, wherein members of the reference population have OA. In some embodiments, the reference population includes at least about 100 subjects. In some embodiments, the reference population includes at least about 200 subjects. In some embodiments, the reference population includes at least about 500 subjects. In some embodiments, the reference population includes at least about 1,000 subjects. In some embodiments, the reference population includes at least about 3,000 subjects. In some embodiments, the reference population includes at least about 5,000 subjects. In some embodiments, the reference population includes at least about 7,500 subjects. In some embodiments, the reference population includes at least about 10,000 subjects. In some embodiments, the reference population includes at least about 12,000 subjects. In some embodiments, the reference population includes at least about 15,000 subjects. In some embodiments, the reference population includes at least about 20,000 subjects. In some embodiments, the reference population includes at least about 30,000 subjects. In some embodiments, the reference population includes at least about 50,000 subjects. In some embodiments, the reference population includes at least about 70,000 subjects. In some embodiments, the reference population includes at least about 100,000 subjects.

[0058] The threshold osteoarthritis proteomic risk score can be determined by a hierarchical structure. In some embodiments, the hierarchical structure can be expressed as percentiles. As a non-limiting example, the osteoarthritis proteomic risk score can be divided into quintiles, such as the top quintile, the top-middle quintile, the middle quintile, the middle-bottom quintile, and the bottom quintile, wherein the top quintile of the osteoarthritis proteomic risk score corresponds to the highest risk group and the bottom quintile of the osteoarthritis proteomic risk score corresponds to the lowest risk group.

[0059] In some embodiments, the threshold osteoarthritis proteomic risk score comprises the highest weighted osteoarthritis proteomic risk score, including but not limited to the top 50%, 55%, 60%, 70%, 80%, 90%, or 95% of the osteoarthritis proteomic risk scores from the subject population. In some embodiments, the threshold osteoarthritis proteomic risk score is a value within the top 50%, 55%, 60%, 70%, 80%, 90%, or 95% percentile. In some embodiments, the threshold osteoarthritis proteomic risk score is a value within the top 50% percentile. In some embodiments, the threshold osteoarthritis proteomic risk score is a value within the top 55% percentile. In some embodiments, the threshold osteoarthritis proteomic risk score is a value within the top 60% percentile. In some embodiments, the threshold osteoarthritis proteomic risk score is a value within the top 65% percentile. In some embodiments, the threshold osteoarthritis proteomic risk score is a value within the top 70% percentile. In some embodiments, the threshold proteomic risk score is a value within the top 75% percentile. In some embodiments, the threshold proteomic risk score is a value within the top 80% percentile. In some embodiments, the threshold proteomic risk score is a value within the top 85% percentile. In some embodiments, the threshold proteomic risk score is a value within the top 90% percentile. In some embodiments, the threshold PRS is a value within the top 95% percentile. In some embodiments, the threshold osteoarthritis proteomic risk score is in the top 75% within a reference population. In some embodiments, the threshold osteoarthritis proteomic risk score is in the top quintile within a reference population.

[0060] Any of the methods described herein may further comprise administering an NGF antagonist and / or a therapeutic agent for treating OA to the subject when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score. In some embodiments, the NGF antagonist comprises an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

[0061] Anti-NGF antibodies can bind to NGF and inhibit NGF biological activity and / or downstream pathways mediated by NGF signaling. Many anti-NGF antibodies are described in, for example, PCT Publication Nos. WO 00 / 073344, WO 02 / 096458, WO 01 / 78698 and WO01 / 64247, U.S. Application Publication No. US2011 / 0206682; U.S. Patent Nos. 5,844,092, 5,877,016 and 6,153,189; Hongo et al., Hybridoma, 2000, 19, 215-227; Cell.Molec.Biol., 1993, 13, 559-568; GenBank Accession Nos. U39608, U39609, L17078 and L17077. In some embodiments, the antibody is ABT-110, Faskinuzumab, Tanezumab, MEDI7352, or Fulanuzumab. In some embodiments, the antibody is Faskinuzumab. In some embodiments, the antibody is Tanezumab. In some embodiments, the antibody is Fulanuzumab. In some embodiments, the antibody is ABT-110.

[0062] Antibodies are intended to refer to immunoglobulin molecules and multimers thereof (e.g., IgM) comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions known as complementarity determining regions (CDRs), interspersed with more conserved regions known as framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of an antibody (or antigen-binding fragment thereof) may be identical to human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on parallel analysis of two or more CDRs.

[0063] Antibodies include antigen-binding fragments (AFs) of complete antibody molecules. The AFs of an antibody or the AFs of an antibody include any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. AFs of an antibody can be derived from complete antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques, which relate to manipulation and expression of DNA encoding antibody variable domains and optional constant domains. Such DNA can be obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains into suitable configurations, or to introduce codons to produce cysteine ​​residues, modify, add or delete amino acids, etc.

[0064] Suitable NGF antagonist polypeptides include, but are not limited to, competitive binding to TrkA or P75 NTR NGF mimetic peptides that target the receptor. Many NGF antagonist peptides are described, for example, in LeSauteur et al., J.Biol.Chem., 1995, 270, 6564-6569; and Brahimi et al., Biochim.Biophys.Acta, 2010, 1800, 1018-1026; and Longo et al., J.Neurosci.Res., 1997, 48, 1-17; PCT Publication Nos. WO 97 / 15593 and WO89 / 09225; and U.S. Pat. No. 6,291,247; and U.S. Pat. No. 6,017,878. Another NGF antagonist is MEDI7352.

[0065] Antisense inhibition involves a decrease in the level of a target nucleic acid in the presence of an oligonucleotide that is complementary to the target nucleic acid compared to the level of the target nucleic acid in the absence of the oligonucleotide.

[0066] Suitable small molecule NGF antagonists are described, for example, in U.S. Publication No. 20010046959. Compounds that inhibit the binding of NGF to p75 are described in PCT Publication No. WO 00 / 69829. Compounds that inhibit the binding of NGF to TrkA / p75 are described in PCT Publication No. WO 98 / 17278. Other examples of NGF antagonists include compounds described in PCT Publication Nos. WO 02 / 17914 and WO 02 / 20479, U.S. Patent Nos. 5,342,942, 6,127,401 and 6,359,130. Other exemplary NGF antagonists are compounds that act as competitive inhibitors of NGF. See U.S. Patent No. 6,291,247. In some embodiments, the small molecule is K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750. In some embodiments, the small molecule is K252a. In some embodiments, the small molecule is ALE-0540. In some embodiments, the small molecule is PQC-083. In some embodiments, the small molecule is PD-90780. In some embodiments, the small molecule is LM11A-31 dihydrochloride. In some embodiments, the small molecule is Y1036. In some embodiments, the small molecule is GZ389988A. In some embodiments, the small molecule is Ro 08-2750.

[0067] Any of the methods described herein may further comprise administering to the subject an NSAID and / or a therapeutic agent for treating OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score. Exemplary NSAIDs include, but are not limited to, ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, or sulindac, or any combination thereof.

[0068] Any of the methods described herein may further comprise administering an opioid and / or a therapeutic agent for treating OA to the subject when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score. Exemplary opioids include, but are not limited to, codeine, hydrocodone, oxycodone, or tramadol, or any combination thereof.

[0069] Any of the methods described herein may further comprise administering to the subject a NaV1.8, NaV1.7 inhibitor and / or a therapeutic agent for treating OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score. Exemplary NaV1.8 and / or Nav 1.7 inhibitors include, but are not limited to, VX-548.

[0070] In some embodiments, therapeutic agents for treating OA may include analgesics, steroid injections, therapeutic injections, antidepressants, physical therapy, strengthening exercises, radiofrequency nerve ablation, or surgery, or any combination thereof.

[0071] Examples of analgesics that can be used to treat OA include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, and sulindac), acetaminophen, glucosamine, chondroitin, and opioids (such as codeine, hydrocodone, oxycodone, or tramadol), or any combination thereof.

[0072] Examples of steroid injections that can be used to treat OA include, but are not limited to, corticosteroids (such as triamcinolone, cortisone, prednisone, and methylprednisolone, or any combination thereof).

[0073] Examples of therapeutic injectables that may be used to treat OA include, but are not limited to, hyaluronic acid injections.

[0074] Examples of antidepressants that may be used to treat OA include, but are not limited to, duloxetine, amitriptyline, desipramine, and nortriptyline, or any combination thereof.

[0075] In some embodiments, treatment of OA may include physical therapy, cognitive behavioral therapy, and / or weight loss.

[0076] An effective amount is an amount sufficient to achieve a beneficial or desired clinical outcome, including relief or reduction in pain sensation. For the purposes of this disclosure, an effective amount of an NGF antagonist (such as an anti-NGF antibody) includes an amount sufficient to treat, ameliorate, reduce pain intensity, or prevent any kind of pain (including nociception and pain sensation), including acute, chronic, inflammatory, neuropathic, or postoperative pain. In some embodiments, the effective amount of an NGF antagonist is an amount of an NGF antagonist that is capable of adjusting the sensitivity threshold to external stimuli to a level comparable to that observed in healthy subjects. In some embodiments, the level may not be comparable to that observed in healthy subjects, but is reduced compared to not receiving the combination therapy. As understood in the art, the effective amount of an NGF antagonist may vary depending on, among other factors, the type of pain (and patient history) and the type (and / or dosage) of NGF antagonist used.

[0077] In the context of the methods disclosed herein, additional therapeutically active ingredients, such as any of the agents listed above or derivatives thereof, may be administered prior to, concurrently with, or shortly after the administration of the NGF antagonist; (for purposes of this disclosure, such administration regimens are considered to be administration of the NGF antagonist "in combination" with the additional therapeutically active ingredients). In some embodiments, the additional therapeutically active ingredients are considered to be administered "in combination" with the NGF antagonist, even though the additional therapeutically active ingredients and the NGF antagonist are administered by different routes. The methods of the present invention include pharmaceutical compositions and methods of use thereof in which an NGF antagonist is co-formulated with one or more additional therapeutically active ingredients as described herein.

[0078] Any of the methods described herein can be used to select a population of subjects or candidates for a clinical trial, for example, a clinical trial whose patient population is suitable for treatment with an NGF antagonist or other OA or pain (such as chronic pain) treatment regimen. In some embodiments, the selected candidates or subjects are divided into subgroups based on the OA proteomic risk score of each subject or candidate, and the method is used to determine whether the subject has an increased risk of developing OA, progressing to TJR, or having a differential pain response. In some embodiments, subjects are selected based solely on the OA proteomic risk score. For example, if a subject or candidate has an OA proteomic risk score greater than or equal to a threshold, the subject is selected to begin treatment or the candidate is included in a clinical trial.

[0079] In addition, in addition to stepwise variable selection, other statistical or machine learning algorithms (including LASSO, elastic net, neural networks, and decision tree-based models such as random forests and XGBoost) can also be applied to construct proteomic risk scores (see Tibshirani, J. Royal Statistical Society, Series B (Methodological), 1996, 58, 267-88; Zou et al., J. Royal Statistical Society, Series B (Statistical Methodology), 2005, 67, 301-320; Castellano et al., Neurocomputing, 2000, 31, 1-13; Ooka et al., BMJ Nutrition, Prevention & Health, 2021, 4, 140-148; and Yan et al., Ann. Transl. Med., 2022, 10, 860).

[0080] All patent documents, websites, other publications, accession numbers, etc. cited above or below are all incorporated herein by reference in their entirety for all purposes, and their extent is specifically and individually pointed out to be so incorporated by reference as each individual project. If the different versions of the sequence are relevant to the accession numbers at different times, it means the version relevant to the accession number of the effective submission date of the application. The effective submission date means the earlier date in the submission date (if applicable) of the priority application of the actual submission date or reference accession number. Similarly, if the different versions of publications, websites, etc. are announced at different times, unless otherwise stated, it means the version recently announced on the effective submission date of the application. Unless otherwise specifically stated, any feature, step, element, embodiment or aspect of the present disclosure can be used in combination with any other feature, step, element, embodiment or aspect. Although the present disclosure has been described in detail by explanation and example for the purpose of clarity and understanding, it will be apparent that some changes and modifications can be implemented within the scope of the appended claims.

[0081] The following examples are provided to describe the embodiments in more detail. They are intended to illustrate but not limit the claimed embodiments. The following examples provide disclosure and description of how the compounds, compositions, products, devices and / or methods described herein are prepared and evaluated for one of ordinary skill in the art, and are intended to be exemplary only and are not intended to limit the scope of any claim. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations may be considered. Unless otherwise stated, parts are parts by weight, temperatures are in ° C or at ambient temperature, and pressures are at or near atmospheric pressure. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the claimed subject matter in any way.

[0082] Example

[0083] Example 1: Proteomic Risk Score Analysis

[0084] Proteomic risk score analysis was performed using serum proteomic data from the UK Biobank (UKB) Pharmaceutical Proteomics Project (PPP), referred to as UKB PPP (Sun et al., bioRxiv, 2022.06.17.496443). A total of 46,431 individuals and 2,939 proteins from the UKB PPP dataset passed quality control and were available for analysis.

[0085] During the initial run of model building in the training data, OA status was used as the response variable, and proteomic data for each protein was used as a predictor, with age, age squared (AgeSq), sex, body mass index (BMI), osteoarthritis polygenic risk score (OA-PRS), and principal components of genetic data as covariates. To account for multiple testing, a Bonferroni correction was used to define a statistical significance cutoff of p = 1.7e-5 (0.05 / 2939). After the initial run of screening, only proteins with a strong association with OA (p value < 1.7e-5) were included as updated candidate proteins. Subsequently, the following two steps were repeated until no protein remained in the protein candidate pool to produce the final selected proteins.

[0086] Step 1: Among the updated candidate proteins, select the protein with the strongest association (smallest p-value) with OA. Subsequently, determine the correlation between the selected proteins and the remaining updated candidate proteins. If there are some proteins with high correlation (>0.8) with the selected proteins, remove these proteins from the updated candidate proteins. Step 2: Add the selected proteins to the covariates and remove them from the candidate proteins. Repeat steps 1 and 2 until no more proteins meet the minimum statistical threshold. Given the updated list of proteins and covariates, the association between the remaining proteins in the candidate pool and OA status can be continuously tested.

[0087] Table 2: Model fits on the UKB PPP training data

[0088]

[0089]

[0090] After all proteins were selected, the prediction model was refitted to the discovery dataset, as shown in Table 2. The final OA proteome score can be calculated as follows: (0.760153 × COL9A1 protein level) + (0.674236 × CRTAC1 protein level) + (−0.259976 × CNTN1 protein level) + (0.075227 × GAST protein level) + (−0.445153 × CYTL1 protein level) + (0.134803 × KLK4 protein level) + (−0.190231 × DLK1 protein level) + (0.147944 × CDCP1 protein level) + (−0.193854 × DPP10 protein level) + (−0.189556 × CELA protein level) 2A protein level) + (0.222883 × RBFOX3 protein level) + (0.182450 × CRELD1 protein level) + (-0.227005 × NELL2 protein level) + (0.099224 × PGA4 protein level) + (-0.099882 × ARG1 protein level) + (-0.247908 × ART3 protein level) + (0.141539 × TIMD4 protein level) + (0.151137 × FGFBP2 protein level) + (-0.063709 × BPIF A2 protein level) + (-0.081213 × PTH protein level) + (0.119394 × BRK1 protein level). Total joint replacement was then used as the endpoint to evaluate the patient stratification strategy for UKB PPP OA patients, as shown in Figure 5. Figure 1 and Figure 2 shown.

[0091] Finally, total joint replacement was also used as an endpoint in the R475-OA-1688 clinical trial to evaluate patient stratification based on OA proteomic scores, such as Figures 3 to 8 Patients in the 1st to 3rd OA proteome score quartiles treated with faskinumab 1q4w showed similar (or lower) percentages of total joint replacements compared with patients in the 1st to 3rd OA proteome score quartiles treated with NSAIDs or placebo.

[0092] Table 3: Percentage of TJR by Treatment Group in R475-OA-1688

[0093]

[0094] In addition to identifying OA patients with a better lower rate of joint replacement progression, patients in the 1st to 3rd OA proteome score quartiles under Faskinumab 1q4w and NSAIDs also exhibited a better efficacy profile (both WOMAC pain and WOMAC function scores), as shown in Figure 9 and Figure 10As shown. Figure 9 and Figure 10 As shown in Table 4, for NSAID-treated patients in the highest risk quartile (quartile 4), the treatment response decreased over time, such that by week 24, NSAID-high-risk patients (quartile 4) exhibited a similar response rate to placebo-treated patients. In addition, Table 4 shows that in patients in the 1st to 3rd OA proteome score quartiles, faskinumab 1q4w maintained its efficacy advantage compared to NSAIDs or placebo.

[0095] Table 4: Improvement in WM pain and function scores at week 24 in the OAPRS Low-risk group (1st-3rd OAPRS quartiles)

[0096]

[0097] Table 5 shows that even in the high-risk OA proteomic score group, faskinumab 1q4w had an efficacy benefit compared with NSAID or placebo-treated patients. NSAID-treated patients in the high-risk OA proteomic score group did not show an improved treatment response compared with placebo-treated patients.

[0098] Table 5: Improvement in WM pain and function scores at week 24 in the OA PRS High-risk group (4th OA PRS quartile)

[0099]

[0100] In addition to the modifications described herein, various modifications to the described themes will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including but not limited to journal articles, U.S. and non-U.S. patents, patent application publications, international patent application publications, gene bank accession numbers, etc.) is incorporated herein by reference in its entirety.

Claims

1. A method of determining a subject's risk of developing osteoarthritis (OA), the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; in: When the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject has an increased risk of developing OA; and When the osteoarthritis proteomic risk score of the subject is less than a threshold osteoarthritis proteomic risk score, the subject has a reduced risk of developing OA.

2. The method of claim 1, wherein the one or more proteins associated with OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acidic protein 1 (CRTA C1), scrapie reactive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA binding protein fox-1 homolog 3 (RBFOX3), decorin (DC N), matrix protein-3 (MATN3), cartilage oligomeric matrix protein (COMP), CUB domain-containing protein 1 (CDCP1), protein BRICK1 (BRK1), gastrin (GAST), collagen alpha-3 (VI) chain (COL6A3), protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), fibroblast growth factor binding protein 2 (FGFBP2), annexin A10 (ANXA10), chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), osteopontin (SPP1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor binding protein 4 (IGFBP4), heart fatty acid binding protein (FABP3), triggering receptor expressed on myeloid cells 2 (TREM2)2), transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-associated protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGRG2), myosin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), slow-type myosin binding protein C (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), mitochondrial protein containing coiled-coil domain 10 (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), Lamin B2 (LMNB2), trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocan core protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b binding protein β chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase 3-like protein 1 (CHI3L1), protein kinase C binding protein NELL2 (NELL2), contact protein 1 (CNTN1), cytoplasmic branched-chain amino acid aminotransferase (BCAT1), transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), natural cytotoxicity triggering receptor 3 ligand 1 (NCR 3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor binding protein 1 (IGFBP1), secretin (SCT), collectin 12 (COLEC12), Prolargin (PRELP), alpha-actinin 2 (ACTN2), tight junction protein (OCLN), galectin 3 (LGALS3), cathepsin L1 (CTSL), dipeptidyl aminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyrotropin subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contact protein 2 (CNTN2), persephin (PSPN), arginase 1 (ARG1), uterine globin SCGB1A1, BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor binding protein 2 (IGFBP2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neural cell adhesion molecule (NRCAM), sushi domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), chelonasin homolog A (IGSF9), tenascin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphokinase 1 (TPK 1), UL16 binding protein 2 (ULBP2), hypoxia up-regulated protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), exo-ADP ribosyltransferase 3 (ART3), protein kinase C binding protein NELL1 (NELL1), macrophage scavenger receptor type I and II (MSR1), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cellular receptor 1 (HAVCR1), peroxidase 2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG 4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuronal protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin B subunit type 1 (PPP3R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), brevican core protein (BCAN), cerebellar peptide 4 (CBLN4), creatine kinase type B (CKB), a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), connexin 2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), uncharacterized protein C9orf40 (C9orf40), protein DDI1 homolog 2 (DDI2), stromelysin 1 (MMP3), adiponectin (ADIPOQ), CMP-N-acetylneuraminic acid-β-galactosamide-α-2,3-sialyltransferase 1 (ST3GAL1), Layilin (LAYN), porphobilinogen dehydrogenase (HMBS), tumor necrosis factor receptor superfamily member 3 (LTBR), lysosomal Pro-X carboxypeptidase (PRCP), centromere protein F (CE NPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myenterin 2 (MYOM 2), receptor tyrosine-protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB 2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin 4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (AS GR2), retinoic acid receptor responsive protein 2 (RARRES2), CC motif chemokine 7 (CCL7), stanniocalcin 1 (STC1), osteocalcin (BGLAP), interleukin 15 (IL15), protein-glutamine gamma-glutamyltransferase 2 (TGM2), latent transforming growth factor beta-binding protein 2 (LTBP2), gamma interferon-induced lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal-type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 (EP HB4), dystrophin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), Mim ecan (OGN), alpha hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), Tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enabled homolog (ENAH), galectin 1 (LGALS1), mitochondrial hydroxyacylglutathione hydrolase (HAGH), fetuin B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), C-type lectin domain family 5 member A (CLEC5A), a disintegrin and metalloproteinase with thrombospondin motif 13 (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family chaperone regulatory protein 3 (BAG3), sclerostin (SOST), Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain-containing protein 80 (CCDC80), odontogenic ameloblast-associated protein (ODAM), cystatin B (CSTB), seizure 6-like protein (SEZ6L), stanniocalcin 2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MX RA8), macrophage capping protein (CAPG), band 3 anion transporter (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (NPPC), cystatin D (CST5), low-density lipoprotein receptor-related protein 1 (LRP1), CC motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1-glycoprotein 1 (PSG1), gastric opsonin (FABP6), ephrin A1 (EFNA1), thrombomodulin (THBD), DnaJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerylphosphatidylcholine choline phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

3. The method of claim 1, wherein the one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH or BRK1, or any combination thereof.

4. The method of any one of claims 1 to 3, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.760153×COL9A1 protein level) + (about 0.674236×CRTAC1 protein level) + (about −0.259976×CNTN1 protein level) + (about 0.075227×GAST protein level) + (about −0.445153×CYTL1 protein level) + (about 0.134803×KLK4 protein level) + (about −0.190231×DLK1 protein level) + (about 0.147944×CDCP1 protein level) + (about −0.193854×DPP10 protein level) + (about −0.189556× (approximately 0.151439 × CELA2A protein level) + (approximately 0.222883 × RBFOX3 protein level) + (approximately 0.182450 × CRELD1 protein level) + (approximately -0.227005 × NELL2 protein level) + (approximately 0.099224 × PGA4 protein level) + (approximately -0.099882 × ARG1 protein level) + (approximately -0.247908 × ART3 protein level) + (approximately 0.141539 × TIMD4 protein level) + (approximately 0.151137 × FGFBP2 protein level) + (approximately -0.063709 × BPIFA2 protein level) + (approximately -0.081213 × PTH protein level) + (approximately 0.119394 × BRK1 protein level).

5. The method of any one of claims 1 to 3, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.7602×COL9A1 protein level) + (about 0.6742×CRTAC1 protein level) + (about −0.2600×CNTN1 protein level) + (about 0.0752×GAST protein level) + (about −0.4452×CYTL1 protein level) + (about 0.1348×KLK4 protein level) + (about −0.1902×DLK1 protein level) + (about 0.1479×CDCP1 protein level) + (about −0.1939×DPP10 protein level) + (about −0.1896×DPP10 protein level) × CELA2A protein level) + (approximately 0.2229 × RBFOX3 protein level) + (approximately 0.1824 × CRELD1 protein level) + (approximately -0.2270 × NELL2 protein level) + (approximately 0.0992 × PGA4 protein level) + (approximately -0.0999 × ARG1 protein level) + (approximately -0.2479 × ART3 protein level) + (approximately 0.1415 × TIMD4 protein level) + (approximately 0.1511 × FGFBP2 protein level) + (approximately -0.0637 × BPIFA2 protein level) + (approximately -0.0812 × PTH protein level) + (approximately 0.1194 × BRK1 protein level).

6. The method of any one of claims 1 to 3, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.76×COL9A1 protein level) + (about 0.67×CRTAC1 protein level) + (about −0.26×CNTN1 protein level) + (about 0.08×GAST protein level) + (about −0.45×CYTL1 protein level) + (about 0.13×KLK4 protein level) + (about −0.19×DLK1 protein level) + (about 0.15×CDCP1 protein level) + (about −0.19×DPP (about -0.10 protein level) + (about -0.19 × CELA2A protein level) + (about 0.22 × RBFOX3 protein level) + (about 0.18 × CRELD1 protein level) + (about -0.23 × NELL2 protein level) + (about 0.10 × PGA4 protein level) + (about -0.10 × ARG1 protein level) + (about -0.25 × ART3 protein level) + (about 0.14 × TIMD4 protein level) + (about 0.15 × FGFBP2 protein level) + (about -0.06 × BPIFA2 protein level) + (about -0.08 × PTH protein level) + (about 0.12 × BRK1 protein level).

7. The method of any one of claims 1 to 6, wherein the osteoarthritis proteomic risk score is determined based on a biological sample obtained from the subject, wherein the biological sample comprises blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, cheek swab, or cells.

8. The method of any one of claims 1 to 7, further comprising administering to the subject a nerve growth factor (NGF) antagonist and / or a therapeutic agent for treating OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score.

9. The method of claim 8, wherein the NGF antagonist is an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, a siRNA molecule, or a small molecule.

10. The method of claim 8, wherein the antibody is Faskinumab, Tanezumab, MEDI7352, or Foranumab.

11. The method of claim 8, wherein the antibody is Fasaki Mab.

12. The method of claim 8, wherein the small molecule is K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

13. A method of determining a subject's risk of progressing to total joint replacement (TJR), the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; in: When the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject has an increased risk of developing TJR; and When the osteoarthritis proteomic risk score of the subject is less than a threshold osteoarthritis proteomic risk score, the risk of the subject developing TJR is reduced.

14. The method of claim 13, wherein the one or more proteins associated with OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acidic protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrix protein-3 (MATN3), cartilage oligomeric matrix protein (COMP), CUB domain-containing protein 1 (CDCP1), and protein BRICK1 (BRK1). , gastrin (GAST), collagen alpha-3 (VI) chain (COL6A3), protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), fibroblast growth factor binding protein 2 (FGFBP2), annexin A10 (ANXA10), chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), osteopontin (SPP1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor binding protein 4 (IGFBP4), heart-type fatty acid binding protein (FAB P3), triggering receptor expressed on myeloid cells 2 (TREM2), transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-associated protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGRG2), myenterin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), slow-type myosin binding protein C (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), mitochondrial protein containing coiled-coil domain 10 (CHCHD10), Myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cellular receptor 2 (HAVCR2), lamin B2 (LMNB2), trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocan core protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b binding protein β chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase 3-like protein 1 (CHI3L1), protein kinase C binding protein NELL2 (NELL2), contact protein 1 (CNTN1),Cytoplasmic branched-chain amino acid aminotransferase (BCAT1), transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), natural cytotoxicity-triggering receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor binding protein 1 (IGFBP1), secretin (SCT), collagen lectin 12 (COLEC12), prolargin (PRELP ), alpha-actin 2 (ACTN2), tight junction protein (OCLN), galectin 3 (LGALS3), cathepsin L1 (CTSL), dipeptidyl aminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyrotropin subunit β (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contact protein 2 (CNTN2), persephin (PSPN), arginase 1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor binding protein 2 (IGFBP 2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neural cell adhesion molecule (NRCAM), sushi domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), turtium homolog A (IGSF9), tenascin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphokinase 1 (TPK1), UL16 binding protein 2 (ULBP2), hypoxia upregulated protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), exo-ADP ribosyltransferase 3 (ART3), protein Kinase C binding protein NELL1 (NELL1), macrophage scavenger receptor type I and II (MSR1), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cellular receptor 1 (HAVCR1), peroxidase 2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuronal protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin B subunit type 1 (PPP3R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9),Brevican core protein (BCAN), cerebellar peptide 4 (CBLN4), creatine kinase type B (CKB), a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), connexin 2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), uncharacterized protein C9orf40 (C9orf40), protein DDI1 homolog 2 (DDI2), stromelysin 1 (MMP3), adiponectin (ADIPOQ), CMP-N-acetylneuraminic acid-β-galactosamide-α-2,3-sialyltransferase 1 (ST3GAL1), Layilin (LAYN), porphobilinogen dehydrogenase (HMBS), tumor necrosis factor receptor superfamily family member 3 (LTBR), lysosomal Pro-X carboxypeptidase (PRCP), centromere protein F (CENPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myenterin 2 (MYOM2), receptor tyrosine-protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin 4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (P HOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor responsive protein 2 (RARRES2), CC motif chemokine 7 (CCL7), stanniocalcin 1 (STC1), osteocalcin (BGLAP), interleukin 15 (IL15), protein-glutamine gamma-glutamyltransferase 2 (TGM2), latent transforming growth factor beta-binding protein 2 (LTBP2), interferon-gamma-induced lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal-type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin-B receptor 4 (EPHB4), dystrophin beta (DTNB), neutrophil cytosolic factor 2 (NCF2), Mimecan (OGN), alpha hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), Tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enabled homolog (ENAH), galectin 1 (LGALS1), mitochondrial hydroxyacylglutathione hydrolase (HAGH), fetuin B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1),C-type lectin domain family 5 member A (CLEC5A), a disintegrin and metalloproteinase with thrombospondin motif 13 (ADAMTS13), cysteine- and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family chaperone regulatory protein 3 (BAG3), sclerostin (SOST), Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain-containing protein 80 (CCDC80), odontogenic ameloblast-associated protein (ODAM), cystatin B (CSTB), seizure 6-like protein (SEZ6L), stanniocalcin 2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1), and cytosine kinase 2 (CTS2). DH1A1), matrix remodeling-associated protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transporter (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (NPPC), cystatin D (CST5), low-density lipoprotein receptor-related protein 1 (LRP1), CC motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1-glycoprotein 1 (PSG1), gastric opsonin (FABP6), ephrin A1 (EFNA1), thrombomodulin (THBD), DnaJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholine choline phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

15. The method of claim 13, wherein the one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

16. The method of any one of claims 13 to 15, wherein the osteoarthritis proteomic risk score is determined by the following formula: (0.76×COL9A1 protein level)+(0.67×CRTAC1 protein level)+(−0.26×CNTN1 protein level)+(0.08×GAST protein level)+(−0.45×CYTL1 protein level)+(0.13×KLK4 protein level)+(−0.19×DLK1 protein level)+(0.15×CDCP1 protein level)+(−0.19×DPP10 protein level)+(−0.19×CELA2A protein level)+(0.22×RBFOX3 protein level)+(0.18×CRELD1 protein level)+(−0.23×NELL2 protein level)+(0.10×PGA4 protein level)+ (-0.10×ARG1 protein level)+(-0.25×ART3 protein level)+(0.14×TIMD4 protein level)+(0.15×FGFBP2 protein level)+(-0.06×BPIFA2 protein level)+(-0.08×PTH protein level)+(0.12×BRK1 protein level).

17. The method of any one of claims 13 to 15, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.76×COL9A1 protein level) + (about 0.67×CRTAC1 protein level) + (about −0.26×CNTN1 protein level) + (about 0.08×GAST protein level) + (about −0.45×CYTL1 protein level) + (about 0.13×KLK4 protein level) + (about −0.19×DLK1 protein level) + (about 0.15×CDCP1 protein level) + (about −0.19×DPP 10 protein level) + (about -0.19 × CELA2A protein level) + (about 0.22 × RBFOX3 protein level) + (about 0.18 × CRELD1 protein level) + (about -0.23 × NELL2 protein level) + (about 0.10 × PGA4 protein level) + (about -0.10 × ARG1 protein level) + (about -0.25 × ART3 protein level) + (about 0.14 × TIMD4 protein level) + (about 0.15 × FGFBP2 protein level) + (about -0.06 × BPIFA2 protein level) + (about -0.08 × PTH protein level) + (about 0.12 × BRK1 protein level).

18. The method of any one of claims 13 to 15, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.8×COL9A1 protein level) + (about 0.7×CRTAC1 protein level) + (about −0.3×CNTN1 protein level) + (about 0.1×GAST protein level) + (about −0.4×CYTL1 protein level) + (about 0.1×KLK4 protein level) + (about −0.2×DLK1 protein level) + (about 0.1×CDCP1 protein level) + (about −0.2×DPP10 protein level) + (about −0.4×CYTL1 protein level) (about 0.2×CELA2A protein level) +(about 0.2×RBFOX3 protein level) +(about 0.2×CRELD1 protein level) +(about -0.2×NELL2 protein level) +(about 0.1×PGA4 protein level) +(about -0.1×ARG1 protein level) +(about -0.2×ART3 protein level) +(about 0.1×TIMD4 protein level) +(about 0.2×FGFBP2 protein level) +(about -0.1×BPIFA2 protein level) +(about -0.1×PTH protein level) +(about 0.1×BRK1 protein level).

19. The method of any one of claims 13 to 18, wherein the osteoarthritis proteomic risk score is determined based on a biological sample obtained from the subject, wherein the biological sample comprises blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, cheek swab, or cells.

20. The method of any one of claims 13 to 19, further comprising administering to the subject a nerve growth factor (NGF) antagonist and / or a therapeutic agent for treating OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score.

21. The method of claim 20, wherein the NGF antagonist is an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

22. The method of claim 21, wherein the antibody is Faskinumab, Tanezumab, MEDI7352, or Foranumab.

23. The method of claim 21, wherein the antibody is Fasaki Mab.

24. The method of claim 21, wherein the small molecule is K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

25. A method of determining a therapeutic response in a subject being treated with a nerve growth factor (NGF) antagonist, the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; in: When the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject is less responsive to an NGF antagonist; and When the subject's osteoarthritis proteomic risk score is less than a threshold osteoarthritis proteomic risk score, the subject's response to the NGF antagonist is increased.

26. The method of claim 25, wherein the one or more proteins associated with OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acidic protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrix protein-3 (MATN3), cartilage oligomeric matrix protein (COMP), CUB domain-containing protein 1 (CDCP1), and protein BRICK1 (BRK1). , gastrin (GAST), collagen alpha-3 (VI) chain (COL6A3), protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), fibroblast growth factor binding protein 2 (FGFBP2), annexin A10 (ANXA10), chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), osteopontin (SPP1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor binding protein 4 (IGFBP4), heart-type fatty acid binding protein (FAB P3), triggering receptor expressed on myeloid cells 2 (TREM2), transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-associated protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGRG2), myenterin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), slow-type myosin binding protein C (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), mitochondrial protein containing coiled-coil domain 10 (CHCHD10), Myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cellular receptor 2 (HAVCR2), lamin B2 (LMNB2), trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocan core protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b binding protein β chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase 3-like protein 1 (CHI3L1), protein kinase C binding protein NELL2 (NELL2), contact protein 1 (CNTN1),Cytoplasmic branched-chain amino acid aminotransferase (BCAT1), transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), natural cytotoxicity-triggering receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor binding protein 1 (IGFBP1), secretin (SCT), collagen lectin 12 (COLEC12), prolargin (PRELP ), alpha-actin 2 (ACTN2), tight junction protein (OCLN), galectin 3 (LGALS3), cathepsin L1 (CTSL), dipeptidyl aminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyrotropin subunit β (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contact protein 2 (CNTN2), persephin (PSPN), arginase 1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor binding protein 2 (IGFBP 2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neural cell adhesion molecule (NRCAM), sushi domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), turtium homolog A (IGSF9), tenascin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphokinase 1 (TPK1), UL16 binding protein 2 (ULBP2), hypoxia upregulated protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), exo-ADP ribosyltransferase 3 (ART3), protein Kinase C binding protein NELL1 (NELL1), macrophage scavenger receptor type I and II (MSR1), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cellular receptor 1 (HAVCR1), peroxidase 2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuronal protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin B subunit type 1 (PPP3R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9),Brevican core protein (BCAN), cerebellar peptide 4 (CBLN4), creatine kinase type B (CKB), a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), connexin 2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), uncharacterized protein C9orf40 (C9orf40), protein DDI1 homolog 2 (DDI2), stromelysin 1 (MMP3), adiponectin (ADIPOQ), CMP-N-acetylneuraminic acid-β-galactosamide-α-2,3-sialyltransferase 1 (ST3GAL1), Layilin (LAYN), porphobilinogen dehydrogenase (HMBS), tumor necrosis factor receptor superfamily family member 3 (LTBR), lysosomal Pro-X carboxypeptidase (PRCP), centromere protein F (CENPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myenterin 2 (MYOM2), receptor tyrosine-protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin 4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (P HOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor responsive protein 2 (RARRES2), CC motif chemokine 7 (CCL7), stanniocalcin 1 (STC1), osteocalcin (BGLAP), interleukin 15 (IL15), protein-glutamine gamma-glutamyltransferase 2 (TGM2), latent transforming growth factor beta-binding protein 2 (LTBP2), interferon-gamma-induced lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal-type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin-B receptor 4 (EPHB4), dystrophin beta (DTNB), neutrophil cytosolic factor 2 (NCF2), Mimecan (OGN), alpha hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), Tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enabled homolog (ENAH), galectin 1 (LGALS1), mitochondrial hydroxyacylglutathione hydrolase (HAGH), fetuin B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1),C-type lectin domain family 5 member A (CLEC5A), a disintegrin and metalloproteinase with thrombospondin motif 13 (ADAMTS13), cysteine- and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family chaperone regulatory protein 3 (BAG3), sclerostin (SOST), Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain-containing protein 80 (CCDC80), odontogenic ameloblast-associated protein (ODAM), cystatin B (CSTB), seizure 6-like protein (SEZ6L), stanniocalcin 2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1), and cytosine kinase 2 (CTS2). DH1A1), matrix remodeling-associated protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transporter (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (NPPC), cystatin D (CST5), low-density lipoprotein receptor-related protein 1 (LRP1), CC motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1-glycoprotein 1 (PSG1), gastric opsonin (FABP6), ephrin A1 (EFNA1), thrombomodulin (THBD), DnaJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholine choline phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

27. The method of claim 25, wherein the one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

28. The method of any one of claims 25 to 27, wherein the osteoarthritis proteomic risk score is determined by the following formula: (0.76×COL9A1 protein level)+(0.67×CRTAC1 protein level)+(-0.26×CNTN1 protein level)+(0.08×GAST protein level)+(-0.45×CYTL1 protein level)+(0.13×KLK4 protein level)+(-0.19×DLK1 protein level)+(0.15×CDCP1 protein level)+(-0.19×DPP10 protein level)+(-0.19×CELA2A protein level)+(0.22×RBFOX3 protein level)+(0.18×CRELD1 protein level)+(-0.23×NELL2 protein level)+(0.10×PGA4 protein level)+(-0.10×ARG 1 protein level) + (-0.25×ART3 protein level) + (0.14×TIMD4 protein level) + (0.15×FGFBP2 protein level) + (-0.06×BPIFA2 protein level) + (-0.08×PTH protein level) + (0.12×BRK1 protein level).

29. The method of any one of claims 25 to 27, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.76×COL9A1 protein level) + (about 0.67×CRTAC1 protein level) + (about −0.26×CNTN1 protein level) + (about 0.08×GAST protein level) + (about −0.45×CYTL1 protein level) + (about 0.13×KLK4 protein level) + (about −0.19×DLK1 protein level) + (about 0.15×CDCP1 protein level) + (about −0.19×DPP10 protein level) + (about −0. (about 19×CELA2A protein level) +(about 0.22×RBFOX3 protein level) +(about 0.18×CRELD1 protein level) +(about -0.23×NELL2 protein level) +(about 0.10×PGA4 protein level) +(about -0.10×ARG1 protein level) +(about -0.25×ART3 protein level) +(about 0.14×TIMD4 protein level) +(about 0.15×FGFBP2 protein level) +(about -0.06×BPIFA2 protein level) +(about -0.08×PTH protein level) +(about 0.12×BRK1 protein level).

30. The method of any one of claims 25 to 27, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.8×COL9A1 protein level) + (about 0.7×CRTAC1 protein level) + (about −0.3×CNTN1 protein level) + (about 0.1×GAST protein level) + (about −0.4×CYTL1 protein level) + (about 0.1×KLK4 protein level) + (about −0.2×DLK1 protein level) + (about 0.1×CDCP1 protein level) + (about −0.2×DPP10 protein level) + (about −0.4×CYTL1 protein level) (about 0.2×CELA2A protein level) +(about 0.2×RBFOX3 protein level) +(about 0.2×CRELD1 protein level) +(about -0.2×NELL2 protein level) +(about 0.1×PGA4 protein level) +(about -0.1×ARG1 protein level) +(about -0.2×ART3 protein level) +(about 0.1×TIMD4 protein level) +(about 0.2×FGFBP2 protein level) +(about -0.1×BPIFA2 protein level) +(about -0.1×PTH protein level) +(about 0.1×BRK1 protein level).

31. The method of any one of claims 25 to 30, wherein the osteoarthritis proteomic risk score is determined based on a biological sample obtained from the subject, wherein the biological sample comprises blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, cheek swab, or cells.

32. The method of any one of claims 25 to 31, wherein the NGF antagonist comprises an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

33. The method of claim 32, wherein the antibody comprises Faskinumab, Tanezumab, MEDI7352, or Foranumab.

34. The method of claim 32, wherein the antibody comprises Fasaki Sakimab.

35. The method of claim 32, wherein the small molecule comprises K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

36. A method of determining a therapeutic response in a subject being treated with a nonsteroidal anti-inflammatory drug (NSAID), the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; in: When the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject's response to an NSAID is reduced; and When the osteoarthritis proteomic risk score of the subject is less than a threshold osteoarthritis proteomic risk score, the subject has an increased response to the NSAID.

37. The method of claim 36, wherein the one or more proteins associated with OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acidic protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrix protein-3 (MATN3), cartilage oligomeric matrix protein (COMP), CUB domain-containing protein 1 (CDCP1), and protein BRICK1 (BRK1). , gastrin (GAST), collagen alpha-3 (VI) chain (COL6A3), protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), fibroblast growth factor binding protein 2 (FGFBP2), annexin A10 (ANXA10), chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), osteopontin (SPP1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor binding protein 4 (IGFBP4), heart-type fatty acid binding protein (FAB P3), triggering receptor expressed on myeloid cells 2 (TREM2), transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-associated protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGRG2), myenterin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), slow-type myosin binding protein C (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), mitochondrial protein containing coiled-coil domain 10 (CHCHD10), Myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cellular receptor 2 (HAVCR2), lamin B2 (LMNB2), trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocan core protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b binding protein β chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase 3-like protein 1 (CHI3L1), protein kinase C binding protein NELL2 (NELL2), contact protein 1 (CNTN1),Cytoplasmic branched-chain amino acid aminotransferase (BCAT1), transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), natural cytotoxicity-triggering receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor binding protein 1 (IGFBP1), secretin (SCT), collagen lectin 12 (COLEC12), prolargin (PRELP ), alpha-actin 2 (ACTN2), tight junction protein (OCLN), galectin 3 (LGALS3), cathepsin L1 (CTSL), dipeptidyl aminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyrotropin subunit β (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contact protein 2 (CNTN2), persephin (PSPN), arginase 1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor binding protein 2 (IGFBP 2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neural cell adhesion molecule (NRCAM), sushi domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), turtium homolog A (IGSF9), tenascin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphokinase 1 (TPK1), UL16 binding protein 2 (ULBP2), hypoxia upregulated protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), exo-ADP ribosyltransferase 3 (ART3), protein Kinase C binding protein NELL1 (NELL1), macrophage scavenger receptor type I and II (MSR1), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cellular receptor 1 (HAVCR1), peroxidase 2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuronal protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin B subunit type 1 (PPP3R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9),Brevican core protein (BCAN), cerebellar peptide 4 (CBLN4), creatine kinase type B (CKB), a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), connexin 2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), uncharacterized protein C9orf40 (C9orf40), protein DDI1 homolog 2 (DDI2), stromelysin 1 (MMP3), adiponectin (ADIPOQ), CMP-N-acetylneuraminic acid-β-galactosamide-α-2,3-sialyltransferase 1 (ST3GAL1), Layilin (LAYN), porphobilinogen dehydrogenase (HMBS), tumor necrosis factor receptor superfamily family member 3 (LTBR), lysosomal Pro-X carboxypeptidase (PRCP), centromere protein F (CENPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myenterin 2 (MYOM2), receptor tyrosine-protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin 4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (P HOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor responsive protein 2 (RARRES2), CC motif chemokine 7 (CCL7), stanniocalcin 1 (STC1), osteocalcin (BGLAP), interleukin 15 (IL15), protein-glutamine gamma-glutamyltransferase 2 (TGM2), latent transforming growth factor beta-binding protein 2 (LTBP2), interferon-gamma-induced lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal-type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin-B receptor 4 (EPHB4), dystrophin beta (DTNB), neutrophil cytosolic factor 2 (NCF2), Mimecan (OGN), alpha hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), Tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enabled homolog (ENAH), galectin 1 (LGALS1), mitochondrial hydroxyacylglutathione hydrolase (HAGH), fetuin B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1),C-type lectin domain family 5 member A (CLEC5A), a disintegrin and metalloproteinase with thrombospondin motif 13 (ADAMTS13), cysteine- and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family chaperone regulatory protein 3 (BAG3), sclerostin (SOST), Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain-containing protein 80 (CCDC80), odontogenic ameloblast-associated protein (ODAM), cystatin B (CSTB), seizure 6-like protein (SEZ6L), stanniocalcin 2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1), and cytosine kinase 2 (CTS2). DH1A1), matrix remodeling-associated protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transporter (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (NPPC), cystatin D (CST5), low-density lipoprotein receptor-related protein 1 (LRP1), CC motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1-glycoprotein 1 (PSG1), gastric opsonin (FABP6), ephrin A1 (EFNA1), thrombomodulin (THBD), DnaJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholine choline phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

38. The method of claim 36, wherein the one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

39. The method of any one of claims 36 to 38, wherein the osteoarthritis proteomic risk score is determined by the following formula: (0.76×COL9A1 protein level)+(0.67×CRTAC1 protein level)+(-0.26×CNTN1 protein level)+(0.08×GAST protein level)+(-0.45×CYTL1 protein level)+(0.13×KLK4 protein level)+(-0.19×DLK1 protein level)+(0.15×CDCP1 protein level)+(-0.19×DPP10 protein level)+(-0. .19×CELA2A protein level)+(0.22×RBFOX3 protein level)+(0.18×CRELD1 protein level)+(-0.23×NELL2 protein level)+(0.10×PGA4 protein level)+(-0.10×ARG1 protein level)+(-0.25×ART3 protein level)+(0.14×TIMD4 protein level)+(0.15×FGFBP2 protein level)+(-0.06×BPIFA2 protein level)+(-0.08×PTH protein level)+(0.12×BRK1 protein level).

40. The method of any one of claims 36 to 38, wherein the osteoarthritis proteomic risk score is determined by the formula: (about 0.76×COL9A1 protein level) + (about 0.67×CRTAC1 protein level) + (about −0.26×CNTN1 protein level) + (about 0.08×GAST protein level) + (about −0.45×CYTL1 protein level) + (about 0.13×KLK4 protein level) + (about −0.19×DLK1 protein level) + (about 0.15×CDCP1 protein level) + (about −0.19×DPP 10 protein level) + (about -0.19 × CELA2A protein level) + (about 0.22 × RBFOX3 protein level) + (about 0.18 × CRELD1 protein level) + (about -0.23 × NELL2 protein level) + (about 0.10 × PGA4 protein level) + (about -0.10 × ARG1 protein level) + (about -0.25 × ART3 protein level) + (about 0.14 × TIMD4 protein level) + (about 0.15 × FGFBP2 protein level) + (about -0.06 × BPIFA2 protein level) + (about -0.08 × PTH protein level) + (about 0.12 × BRK1 protein level).

41. The method of any one of claims 36 to 38, wherein the osteoarthritis proteomic risk score is determined by the following formula: (about 0.8×COL9A1 protein level) + (about 0.7×CRTAC1 protein level) + (about −0.3×CNTN1 protein level) + (about 0.1×GAST protein level) + (about −0.4×CYTL1 protein level) + (about 0.1×KLK4 protein level) + (about −0.2×DLK1 protein level) + (about 0.1×CDCP1 protein level) + (about −0.2×DPP10 protein level) + (about −0.4×CYTL1 protein level) (about 0.2×CELA2A protein level) +(about 0.2×RBFOX3 protein level) +(about 0.2×CRELD1 protein level) +(about -0.2×NELL2 protein level) +(about 0.1×PGA4 protein level) +(about -0.1×ARG1 protein level) +(about -0.2×ART3 protein level) +(about 0.1×TIMD4 protein level) +(about 0.2×FGFBP2 protein level) +(about -0.1×BPIFA2 protein level) +(about -0.1×PTH protein level) +(about 0.1×BRK1 protein level).

42. The method of any one of claims 36 to 41, wherein the osteoarthritis proteomic risk score is determined based on a biological sample obtained from the subject, wherein the biological sample comprises blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, cheek swab, or cells.

43. The method of any one of claims 36 to 42, wherein the NSAID comprises ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, or sulindac, or any combination thereof.

44. A method of determining a subject's response to treatment (pain and functional improvement), the method comprising: determining or having determined an osteoarthritis proteomic risk score for the subject, wherein the osteoarthritis proteomic risk score comprises a weighted sum of expression levels or circulating levels of one or more proteins associated with OA; in: When the subject's osteoarthritis proteomic risk score is greater than or equal to a threshold osteoarthritis proteomic risk score, the subject has a lesser treatment response; and When the osteoarthritis proteomic risk score of the subject is less than a threshold osteoarthritis proteomic risk score, the treatment response of the subject is increased.

45. The method of claim 44, wherein the one or more proteins associated with OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acidic protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrix protein-3 (MATN3), cartilage oligomeric matrix protein (COMP), CUB domain-containing protein 1 (CDCP1), and protein BRICK1 (BRK1). , gastrin (GAST), collagen alpha-3 (VI) chain (COL6A3), protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), fibroblast growth factor binding protein 2 (FGFBP2), annexin A10 (ANXA10), chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), osteopontin (SPP1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor binding protein 4 (IGFBP4), heart-type fatty acid binding protein (FAB P3), triggering receptor expressed on myeloid cells 2 (TREM2), transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-associated protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGRG2), myenterin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), slow-type myosin binding protein C (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), mitochondrial protein containing coiled-coil domain 10 (CHCHD10), Myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cellular receptor 2 (HAVCR2), lamin B2 (LMNB2), trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocan core protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b binding protein β chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase 3-like protein 1 (CHI3L1), protein kinase C binding protein NELL2 (NELL2), contact protein 1 (CNTN1),Cytoplasmic branched-chain amino acid aminotransferase (BCAT1), transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), natural cytotoxicity-triggering receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor binding protein 1 (IGFBP1), secretin (SCT), collagen lectin 12 (COLEC12), prolargin (PRELP ), alpha-actin 2 (ACTN2), tight junction protein (OCLN), galectin 3 (LGALS3), cathepsin L1 (CTSL), dipeptidyl aminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyrotropin subunit β (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contact protein 2 (CNTN2), persephin (PSPN), arginase 1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor binding protein 2 (IGFBP 2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neural cell adhesion molecule (NRCAM), sushi domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), turtium homolog A (IGSF9), tenascin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphokinase 1 (TPK1), UL16 binding protein 2 (ULBP2), hypoxia upregulated protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), exo-ADP ribosyltransferase 3 (ART3), protein Kinase C binding protein NELL1 (NELL1), macrophage scavenger receptor type I and II (MSR1), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cellular receptor 1 (HAVCR1), peroxidase 2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuronal protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin B subunit type 1 (PPP3R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9),Brevican core protein (BCAN), cerebellar peptide 4 (CBLN4), creatine kinase type B (CKB), a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), connexin 2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), uncharacterized protein C9orf40 (C9orf40), protein DDI1 homolog 2 (DDI2), stromelysin 1 (MMP3), adiponectin (ADIPOQ), CMP-N-acetylneuraminic acid-β-galactosamide-α-2,3-sialyltransferase 1 (ST3GAL1), Layilin (LAYN), porphobilinogen dehydrogenase (HMBS), tumor necrosis factor receptor superfamily family member 3 (LTBR), lysosomal Pro-X carboxypeptidase (PRCP), centromere protein F (CENPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myenterin 2 (MYOM2), receptor tyrosine-protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin 4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (P HOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor responsive protein 2 (RARRES2), CC motif chemokine 7 (CCL7), stanniocalcin 1 (STC1), osteocalcin (BGLAP), interleukin 15 (IL15), protein-glutamine gamma-glutamyltransferase 2 (TGM2), latent transforming growth factor beta-binding protein 2 (LTBP2), interferon-gamma-induced lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal-type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin-B receptor 4 (EPHB4), dystrophin beta (DTNB), neutrophil cytosolic factor 2 (NCF2), Mimecan (OGN), alpha hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), Tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enabled homolog (ENAH), galectin 1 (LGALS1), mitochondrial hydroxyacylglutathione hydrolase (HAGH), fetuin B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1),C-type lectin domain family 5 member A (CLEC5A), a disintegrin and metalloproteinase with thrombospondin motif 13 (ADAMTS13), cysteine- and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family chaperone regulatory protein 3 (BAG3), sclerostin (SOST), Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain-containing protein 80 (CCDC80), odontogenic ameloblast-associated protein (ODAM), cystatin B (CSTB), seizure 6-like protein (SEZ6L), stanniocalcin 2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1), and cytosine kinase 2 (CTS2). DH1A1), matrix remodeling-associated protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transporter (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (NPPC), cystatin D (CST5), low-density lipoprotein receptor-related protein 1 (LRP1), CC motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1-glycoprotein 1 (PSG1), gastric opsonin (FABP6), ephrin A1 (EFNA1), thrombomodulin (THBD), DnaJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholine choline phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

46. ​​The method of claim 44, wherein the one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

47. The method of any one of claims 44 to 46, wherein the osteoarthritis proteomic risk score is determined by the following formula: (0.76×COL9A1 protein level)+(0.67×CRTAC1 protein level)+(-0.26×CNTN1 protein level)+(0.08×GAST protein level)+(-0.45×CYTL1 protein level)+(0.13×KLK4 protein level)+(-0.19×DLK1 protein level)+(0.15×CDCP1 protein level)+(-0.19×DPP10 protein level)+(-0.19×CELA2A protein level)+(0.22×RBFOX3 protein level)+(0.18×CRELD1 protein level)+(-0.23×NELL2 protein level)+(0.10×PGA4 protein level)+(-0.10×ARG 1 protein level) + (-0.25×ART3 protein level) + (0.14×TIMD4 protein level) + (0.15×FGFBP2 protein level) + (-0.06×BPIFA2 protein level) + (-0.08×PTH protein level) + (0.12×BRK1 protein level).

48. The method of any one of claims 44 to 46, wherein the osteoarthritis proteomic risk score is determined by the formula: (about 0.76×COL9A1 protein level) + (about 0.67×CRTAC1 protein level) + (about −0.26×CNTN1 protein level) + (about 0.08×GAST protein level) + (about −0.45×CYTL1 protein level) + (about 0.13×KLK4 protein level) + (about −0.19×DLK1 protein level) + (about 0.15×CDCP1 protein level) + (about −0.19×DPP 10 protein level) + (about -0.19 × CELA2A protein level) + (about 0.22 × RBFOX3 protein level) + (about 0.18 × CRELD1 protein level) + (about -0.23 × NELL2 protein level) + (about 0.10 × PGA4 protein level) + (about -0.10 × ARG1 protein level) + (about -0.25 × ART3 protein level) + (about 0.14 × TIMD4 protein level) + (about 0.15 × FGFBP2 protein level) + (about -0.06 × BPIFA2 protein level) + (about -0.08 × PTH protein level) + (about 0.12 × BRK1 protein level).

49. The method of any one of claims 44 to 46, wherein the osteoarthritis proteomic risk score is determined by the formula: (about 0.8×COL9A1 protein level) + (about 0.7×CRTAC1 protein level) + (about −0.3×CNTN1 protein level) + (about 0.1×GAST protein level) + (about −0.4×CYTL1 protein level) + (about 0.1×KLK4 protein level) + (about −0.2×DLK1 protein level) + (about 0.1×CDCP1 protein level) + (about −0.2×DPP10 protein level) + (about −0.4×CYTL1 protein level) (about 0.2×CELA2A protein level) +(about 0.2×RBFOX3 protein level) +(about 0.2×CRELD1 protein level) +(about -0.2×NELL2 protein level) +(about 0.1×PGA4 protein level) +(about -0.1×ARG1 protein level) +(about -0.2×ART3 protein level) +(about 0.1×TIMD4 protein level) +(about 0.2×FGFBP2 protein level) +(about -0.1×BPIFA2 protein level) +(about -0.1×PTH protein level) +(about 0.1×BRK1 protein level).

50. The method of any one of claims 44 to 49, wherein the osteoarthritis proteomic risk score is determined based on a biological sample obtained from the subject, wherein the biological sample comprises blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, cheek swab, or cells.

51. The method of any one of claims 44 to 50, further comprising administering to the subject a nerve growth factor (NGF) antagonist and / or a therapeutic agent for treating OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score.

52. The method of claim 51, wherein the NGF antagonist comprises an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

53. The method of claim 52, wherein the antibody comprises Faskinumab, Tanezumab, MEDI7352, or Foranumab.

54. The method of claim 53, wherein the antibody comprises Fasaki Sakimab.

55. The method of claim 52, wherein the small molecule comprises K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

56. The method of any one of claims 44 to 50, further comprising administering to the subject a nonsteroidal anti-inflammatory drug (NSAID) and / or a therapeutic agent to treat OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score.

57. The method of claim 56, wherein the NSAID comprises ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, or sulindac, or any combination thereof.

58. The method of any one of claims 44 to 50, further comprising administering an opioid and / or a therapeutic agent to treat OA to the subject when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score.

59. The method of claim 58, wherein the opioid comprises codeine, hydrocodone, oxycodone, or tramadol, or any combination thereof.

60. The method of any one of claims 44 to 50, further comprising administering to the subject a NaV1.8, NaV1.7 inhibitor, and / or a therapeutic agent for treating OA when the subject's osteoarthritis proteomic risk score is less than or equal to a threshold osteoarthritis proteomic risk score.

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