Method for evaluating pharmacological action of immune checkpoint inhibitors, calculation method, evaluation device, calculation device, evaluation program, calculation program, recording medium, evaluation system, and terminal device

Abstract

The present invention addresses the problem of providing an evaluation method capable of providing highly reliable information which can be a reference to finding individual differences in the expression of the pharmacological action of an immune check point inhibitor. The present embodiment evaluates the pharmacological action of the immune check point inhibitor in a subject under evaluation by using a concentration value of at least one metabolite among Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot and XA in the blood of the subject to be evaluated.

Description

[Technical field]

[0001] The present invention relates to a method for evaluating the pharmacological action of an immune checkpoint inhibitor, a calculation method, an evaluation device, a calculation device, an evaluation program, a calculation program, a recording medium, an evaluation system, and a terminal device. [Background technology]

[0002] Immune checkpoint inhibitor therapy is a method of treating cancer by releasing the immunosuppressive state caused by cancer and normalizing the body's immune function, and has been shown to be effective in various types of cancer, including malignant melanoma, non-small cell lung cancer, small cell lung cancer, malignant pleural splenomegaly, renal cell carcinoma, Hodgkin's lymphoma, Merkel cell carcinoma, urothelial carcinoma, head and neck cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, breast cancer, and bladder cancer. Immune checkpoint inhibitor therapy has an accumulating track record, with cases of cure reported even for advanced and recurrent cancers that are difficult to cure with conventional treatments, and it is becoming more and more popular as a fourth treatment method in addition to conventional treatments such as surgery, radiation therapy, and chemotherapy.

[0003] However, several issues have become clear regarding immune checkpoint inhibitor therapy. Specifically, while there are patients for whom the therapy is extremely effective, only 20-30% of patients show long-term efficacy. In addition, immune-related adverse events (irAEs) occur, and medical costs are higher than with conventional therapies. Therefore, diagnostic techniques are needed to select patients who should be treated with immune checkpoint inhibitor therapy.

[0004] Conventional companion diagnostics used to select immune checkpoint inhibitor therapy mainly use indicators obtained from tumor tissue (e.g., the presence or absence of immunosuppressive molecules such as PD-L1 molecules, cancer gene mutations, or microsatellite instability) to select patient treatment. However, it has been reported that the mechanism by which cancer immune responses are suppressed involves interactions with various immunosuppressive molecules and immunosuppressive cell functions. Therefore, the development of new biomarkers is required to accurately predict the effectiveness of treatment.

[0005] Amino acids are universal nutrients that are used as substrates and energy sources for biological components such as proteins and nucleic acids, and are essential for controlling cancer cell proliferation and immune cell function. It is believed that the increased utilization of amino acids in energy metabolism due to cancer cell proliferation, the protein catabolic state occurring in organs throughout the body, and amino acid metabolic abnormalities mediated by various immune regulatory cells result in a competitive state of amino acids necessary for immune responses against cancer, such as cysteine, glutamine, phenylalanine, tryptophan, and arginine, which is thought to lead to immune evasion of cancer (Non-Patent Document 1). In addition, it has been reported that the mechanism of interaction between cancer and immunity is that myeloid-derived immunosuppressive cells (MDSCs), arginine decomposition enzymes (arginase) expressed in tumor-infiltrating macrophages, and tryptophan metabolic enzymes (IDO), etc., deplete amino acids, resulting in the suppression of immune cell function, and that amino acid metabolic enzymes such as IDO and histidine decarboxylase (HDC) are involved in the regulation of regulatory T cell (Treg) function (Non-Patent Documents 1-4). In addition, a method for evaluating the function of MDSC, which is related to the prognosis of critically ill patients, by analyzing arginine in the blood has been presented (Non-Patent Document 5). More recently, quinolinic acid, a tryptophan metabolite mediated by IDO, and a combination of tryptophan and kynurenine have been reported as indicators for predicting the prognosis of immune checkpoint inhibitor treatment (Non-Patent Document 6). It has also been reported that activation of such tryptophan metabolic pathways can be a prognostic indicator of immune checkpoint inhibitor treatment in malignant melanoma and renal cell carcinoma, suggesting the possibility that a common immunosuppressive mechanism is at work in various cancer types (Non-Patent Document 7).

[0006] Furthermore, Patent Document 1 has been published relating to a method for evaluating the therapeutic effect of cancer immunotherapy using amino acid concentrations. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2013 / 168550 [Non-patent literature]

[0008] [Non-Patent Document 1] Sikalidis AK., Amino Acids and Immune Response: A Role for Cysteine, Glutamine, Phenylalanine, Tryptophan and Arginine in T-cell Function and Cancer?, Pathol Oncol Res., 2015: 21: 9 [Non-Patent Document 2] Raber P, Ochoa AC, Rodriguez PC., Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives., Immunol Invest., 2012; 41(6-7): 614 [Non-Patent Document 3] Sharma MD, Baban B, Chandler P et al., Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase., J Clin Invest., 2007; 117(9): 2570 [Non-Patent Document 4] Tamaka K, Seike M, Hagiwara T et al., Histamine suppresses regulatory T cells mediated by TGF-β in murine chronic allergic contact dermatitis., Exp Dermatol., 2015; 24(4): 280 [Non-Patent Document 5] Gey A, Tadie JM, Caumont-Prim A et al., Granulocytic myeloid-derived suppressor cells inversely correlate with plasma arginine and overall survival in critically ill patients., Clinical and Experimental Immunology, 2014; 180: 280-288 [Non-Patent Document 6] Botticelli A, Cerbelli B, Lionetto L et al., Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?, J Transl Med., 2018; 16(1): 219 [Non-Patent Document 7] Li H, Bullock K, Gurjao C et al., Metabolomic adaptations and correlates of survival to immune checkpoint blockade., Nat Commun., 2019; 10(1): 4346 Summary of the Invention [Problem to be solved by the invention]

[0009] If it were possible to accurately determine or predict the prognosis of treatment and the risk of side effects before or soon after the start of immune checkpoint inhibitor treatment, it would be possible to more accurately select a treatment suitable for each patient, which would ultimately lead to improved outcomes of immune checkpoint inhibitor treatment. In addition, for patients for whom immune checkpoint inhibitor treatment is predicted to be ineffective, there is the benefit of being able to avoid unnecessary treatment costs and side effects, as well as the benefit of having the opportunity to select a different treatment at an early stage. It is expected that the promotion of personalized medicine will also be of great help in improving medical economics.

[0010] However, Non-Patent Documents 1-4 do not discuss the possibility of evaluating local changes in immune cell function using metabolites in blood. Non-Patent Document 5 does not relate to the evaluation of local immune responses caused by cancer. Non-Patent Document 6 does not provide sufficient discrimination accuracy. Patent Document 1 does not show that it is possible to predict the prognosis of immune checkpoint inhibitor treatment.

[0011] In other words, biomarkers using amino acids or amino acid-related metabolites in the blood that can accurately determine or predict the prognosis of immune checkpoint inhibitor treatment or the risk of side effects have not yet been developed.

[0012] The present invention has been made in consideration of the above problems, and aims to provide an evaluation method, a calculation method, an evaluation device, a calculation device, an evaluation program, a calculation program, a recording medium, an evaluation system, and a terminal device that can provide reliable information that can be useful in knowing individual differences in the pharmacological effects of immune checkpoint inhibitors. [Means for solving the problem]

[0013] In order to solve the above-mentioned problems and achieve the object, the evaluation method of the present invention is characterized in that it includes an evaluation step of evaluating the pharmacological action of an immune checkpoint inhibitor in the subject using the concentration value of at least one metabolite among 21 types of amino acids (Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp and Gly) and 15 types of amino acid-related metabolites (AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot and XA) in the blood of the subject, or an equation including variables into which the concentration value is substituted and the value of the equation calculated using the concentration value.

[0014] Here, in the present specification, immune checkpoint inhibitors include PD-1 inhibitors (such as nivolumab or pembrolizumab), PD-L1 inhibitors (such as atezolizumab or duvalumab), and CTLA-4 inhibitors (such as ipilimumab). In addition, in the present specification, pharmacological action includes pharmacological action (main action) and general pharmacological action (side effect).

[0015] In addition, various amino acids and various amino acid-related metabolites are mainly represented by abbreviations in this specification, but their official names are as follows. (Abbreviation) (Official name) Ala Alanine AnthA Anthranic Acid Arg Arginine Asparagine ABA α-Aminobutyric acid Cit Citrulline Gln Glutamine Glutamic acid Gly Glycine hAnthA 3-Hydroxy Anthranilic Acid hIAA 5-Hydroxy Indol 3-Acetic Acid His Histidine hKyn hydroxy Kynurenine hTrp 5-hydroxy Tryptophan IAA Indol 3-Acetic Acid ILA Indol 3-Lactic Acid Isoleucine Kyn Kynurenine KynA Kynurenic Acid Leu Leucine Lysine Methionine NFKyn N-Formyl Kynurenine NP Neopterin Orn Ornithine PA Picolinic Acid Phe Phenylalanine Proline QA Quinolinic Acid Ser Serine Serotonin Thr Threonine Trp Tryptophan Tyr Tyrosine Val Valine XA Xanthurenic Acid

[0016] Furthermore, the evaluation method of the present invention is characterized in that, in the evaluation method, the blood is collected from the evaluation subject before or after treatment with the immune checkpoint inhibitor is started, and the evaluation step evaluates the effect of the treatment in the evaluation subject.

[0017] Here, in the present specification, "before treatment is started" may be written as "before treatment" or "before treatment is started", and "after treatment is started" may be written as "after treatment is started". In addition, in the present specification, "before treatment is started" may include, for example, before the first narrow treatment in a broad treatment over a certain period of time is performed. In addition, in the present specification, "after treatment is started" may include, for example, after the first narrow treatment in a broad treatment over a certain period of time and before the final narrow treatment (for example, commonly referred to as "during treatment"), or after the final narrow treatment in a broad treatment over a certain period of time is performed (for example, commonly referred to as "after treatment").

[0018] Furthermore, the evaluation method of the present invention is characterized in that, in the evaluation method, the blood is collected from the evaluation subject before treatment with the immune checkpoint inhibitor is started, and the evaluation step evaluates the risk of side effects due to the treatment in the evaluation subject.

[0019] Moreover, in the evaluation method according to the present invention, the evaluation step is executed in a control unit of an information processing device including a control unit.

[0020] Furthermore, the calculation method of the present invention is characterized by including a calculation step of calculating the value of an equation for evaluating the pharmacological action of an immune checkpoint inhibitor, the equation including concentration values ​​of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of the subject to be evaluated, and variables into which the concentration values ​​are substituted.

[0021] Furthermore, the calculation method of the present invention is characterized in that, in the calculation method, the blood is collected from the subject to be evaluated before or after treatment with the immune checkpoint inhibitor is started, and the formula is for evaluating the effect of the treatment.

[0022] Furthermore, the calculation method of the present invention is characterized in that, in the calculation method, the blood is collected from the subject to be evaluated before treatment with the immune checkpoint inhibitor is started, and the formula is for evaluating the risk of side effects due to the treatment.

[0023] Moreover, in the calculation method according to the present invention, the calculation step is executed in a control unit of an information processing device including a control unit.

[0024] Furthermore, the evaluation device of the present invention is characterized in that it is an evaluation device equipped with a control unit, and the control unit is equipped with evaluation means for evaluating the pharmacological action of an immune checkpoint inhibitor in the subject, using a concentration value of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of the subject, or a formula including a variable into which the concentration value is substituted and the value of the formula calculated using the concentration value.

[0025] Moreover, the evaluation device according to the present invention is communicatively connected via a network to a terminal device that provides concentration data relating to the concentration value or the value of the formula, and the control unit further includes a data receiving means for receiving the concentration data or the value of the formula transmitted from the terminal device, and a result transmitting means for transmitting the evaluation result obtained by the evaluation means to the terminal device, and the evaluation means uses the concentration value or the value of the formula contained in the concentration data received by the data receiving means.

[0026] Furthermore, the calculation device according to the present invention is characterized in that it is a calculation device equipped with a control unit, and the control unit is equipped with a calculation means for calculating the value of an equation for evaluating the pharmacological action of an immune checkpoint inhibitor, the equation including concentration values ​​of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of a subject to be evaluated, and a variable into which the concentration values ​​are substituted.

[0027] Furthermore, the evaluation program of the present invention is an evaluation program to be executed in an information processing device having a control unit, and is characterized in that it includes an evaluation step for evaluating the pharmacological action of an immune checkpoint inhibitor in the subject to be evaluated using a concentration value of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of the subject to be evaluated, or an equation including a variable into which the concentration value is substituted, and the value of the equation calculated using the concentration value, to be executed in the control unit.

[0028] Furthermore, the calculation program of the present invention is a calculation program to be executed in an information processing device having a control unit, and is characterized in that it includes a calculation step of calculating the value of an equation for evaluating the pharmacological action of an immune checkpoint inhibitor, the equation including concentration values ​​of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of a subject to be evaluated, and a variable into which the concentration value is substituted, using the equation to be executed in the control unit.

[0029] The recording medium according to the present invention is a computer-readable recording medium having the evaluation program or the calculation program recorded therein. Specifically, the recording medium according to the present invention is a non-transitory computer-readable recording medium, and is characterized in that it includes programmed instructions for causing an information processing device to execute the evaluation method or the calculation method.

[0030] Furthermore, the evaluation system according to the present invention is an evaluation system configured by connecting an evaluation device having a control unit and a terminal device having a control unit via a network so that they can communicate with each other, wherein the control unit of the terminal device comprises: a data transmitting means for transmitting to the evaluation device concentration data on concentration values ​​of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of a subject to be evaluated, or a formula including a variable into which the concentration values ​​are substituted and a value of the formula calculated using the concentration values; and a result receiving means for receiving an evaluation result on the pharmacological action of an immune checkpoint inhibitor transmitted from the evaluation device, and the control unit of the evaluation device comprises: a data receiving means for receiving the concentration data or the value of the formula transmitted from the terminal device; an evaluation means for evaluating the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated using the concentration value or the value of the formula contained in the concentration data received by the data receiving means; and a result transmitting means for transmitting the evaluation result obtained by the evaluation means to the terminal device.

[0031] Furthermore, a terminal device according to the present invention is a terminal device equipped with a control unit, the control unit being equipped with a result acquisition means for acquiring evaluation results regarding the pharmacological action of an immune checkpoint inhibitor, and the evaluation result is a result of evaluating the pharmacological action of the immune checkpoint inhibitor in the evaluation subject using a concentration value of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of the evaluation subject, or an equation including a variable into which the concentration value is substituted and the value of the equation calculated using the concentration value.

[0032] Furthermore, the terminal device of the present invention is communicatively connected via a network to an evaluation device that evaluates the pharmacological action of an immune checkpoint inhibitor, the control unit includes a data transmission means that transmits concentration data regarding the concentration value or the value of the formula to the evaluation device, and the result acquisition means receives the evaluation result transmitted from the evaluation device. Effect of the Invention

[0033] The present invention has the effect of providing highly reliable information that can be useful in understanding individual differences in the pharmacological effects of immune checkpoint inhibitors. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 is a diagram showing the basic principle of the first embodiment. [Diagram 2] FIG. 2 is a diagram showing the basic principle of the second embodiment. [Diagram 3] FIG. 3 is a diagram showing an example of the overall configuration of the present system. [Figure 4] FIG. 4 is a diagram showing another example of the overall configuration of the present system. [Diagram 5] FIG. 5 is a block diagram showing an example of the configuration of the evaluation device 100 of this system. [Figure 6] FIG. 6 is a diagram showing an example of information stored in the concentration data file 106a. [Figure 7] FIG. 7 is a diagram showing an example of information stored in the index state information file 106b. [Figure 8] FIG. 8 is a diagram showing an example of information stored in the designated index state information file 106c. [Figure 9] FIG. 9 is a diagram showing an example of information stored in the formula file 106d1. [Figure 10] FIG. 10 is a diagram showing an example of information stored in the evaluation result file 106e. [Figure 11] FIG. 11 is a block diagram showing the configuration of the evaluation unit 102d. [Figure 12] FIG. 12 is a block diagram showing an example of the configuration of a client device 200 of this system. [Figure 13] FIG. 13 is a block diagram showing an example of the configuration of the database device 400 of this system. [Figure 14] FIG. 14 is a diagram showing the concentration values ​​of each amino acid and each amino acid-related metabolite, etc. [Figure 15] FIG. 15 shows the analysis results obtained in multivariate analysis using the univariate Cox hazard model. [Figure 16] FIG. 16 shows the analysis results obtained in multivariate analysis using the univariate Cox hazard model. [Figure 17] FIG. 17 shows the distribution of C-Index for the two-variable discriminant, the three-variable discriminant, the four-variable discriminant, the five-variable discriminant, and the six-variable discriminant. [Figure 18] FIG. 18 is a diagram showing the frequency of occurrence of amino acid variables in discriminants. [Figure 19] FIG. 19 is a diagram showing the frequency of appearance of amino acid variables and amino acid-related metabolite variables in discriminants. [Figure 20] FIG. 20 is a diagram showing the frequency of occurrence of amino acid variables in discriminants. [Figure 21] FIG. 21 is a diagram showing the frequency of appearance of amino acid variables and amino acid-related metabolite variables in discriminants. [Figure 22] FIG. 22 is a diagram showing the discrimination performance of a discriminant created by a stepwise method with the goal of minimizing AIC (Akaike Information Criterion). [Diagram 23] FIG. 23 shows the analysis results obtained in multivariate analysis using a univariate logistic regression model. [Figure 24] FIG. 24 shows the distribution of AOC_AUC for a discriminant with two variables, a discriminant with three variables, a discriminant with four variables, a discriminant with five variables, and a discriminant with six variables. [Diagram 25] FIG. 25 is a diagram showing the frequency of occurrence of amino acid variables in discriminants. [Figure 26] FIG. 26 is a diagram showing the frequency of appearance of amino acid variables and amino acid-related metabolite variables in discriminants. [Figure 27] FIG. 27 shows the analysis results obtained in multivariate analysis using the univariate Cox hazard model. [Figure 28] FIG. 28 shows the analysis results obtained by univariate correlation analysis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Hereinafter, an embodiment (first embodiment) of the evaluation method according to the present invention, and an embodiment (second embodiment) of the evaluation device, evaluation method, evaluation program, recording medium, evaluation system, and terminal device according to the present invention will be described in detail with reference to the drawings. Note that the present invention is not limited to these embodiments.

[0036] [First embodiment] [1-1. Overview of the first embodiment] Here, an overview of the first embodiment will be described with reference to Fig. 1. Fig. 1 is a diagram showing the basic principle of the first embodiment.

[0037] First, concentration data is obtained regarding the concentration values ​​of at least one of the 21 types of amino acids and the 15 types of amino acid-related metabolites in blood (including, for example, plasma, serum, etc.) collected from a subject (e.g., an individual such as an animal or human) with cancer who may be a candidate for treatment with an immune checkpoint inhibitor (step S11).

[0038] Here, "potentially becoming a subject to receive treatment" means, for example, that there is a possibility of selecting the treatment or that the treatment is planned.

[0039] In step S11, for example, concentration data derived from blood collected from the subject before the start of cancer treatment (e.g., treatment by surgical therapy, chemotherapy, radiation therapy, or cancer immunotherapy) (concentration data before the start of treatment) and concentration data derived from blood collected after the start of the treatment (concentration data after the start of treatment) may be acquired. Note that "before the start of treatment" includes, for example, before the first narrow-sense treatment in a broad-sense treatment over a certain period of time is performed. Also, "after the start of treatment" includes, for example, after the first narrow-sense treatment in a broad-sense treatment over a certain period of time and before the final narrow-sense treatment (e.g., commonly referred to as "during treatment"), or after the final narrow-sense treatment in a broad-sense treatment over a certain period of time is performed (e.g., commonly referred to as "after treatment").

[0040] In step S11, concentration data measured by a company or the like that measures concentration values ​​may be obtained. Concentration data may also be obtained by measuring the concentration value from blood collected from the subject to be evaluated using the following measurement method (A), (B), or (C), for example. Here, the unit of the concentration value may be, for example, molar concentration, weight concentration, or enzyme activity, or may be obtained by adding, subtracting, multiplying, or dividing any constant by these concentrations. (A) Plasma is separated from blood by centrifuging the collected blood sample. All plasma samples are frozen and stored at -80 ° C. until the concentration value is measured. When measuring the concentration value, acetonitrile is added to perform deproteinization treatment, and then impurities such as phospholipids are removed by solid phase extraction or the like as necessary, and pre-column derivatization is performed using a labeling reagent (3-aminopyridyl-N-hydroxysuccinimidyl carbamate), and the concentration value is analyzed by liquid chromatography mass spectrometry (LC / MS) (see International Publication No. 2003 / 069328, International Publication No. 2005 / 116629, or non-patent document "Chromatography 2019, 40, 127-133"). (B) The collected blood samples are centrifuged to separate plasma from the blood. All plasma samples are frozen and stored at -80°C until the concentration values ​​are measured. When measuring the concentration values, sulfosalicylic acid is added to remove proteins, and then the concentration values ​​are analyzed using an amino acid analyzer based on the post-column derivatization method using ninhydrin reagent. (C) The collected blood sample is subjected to blood cell separation using membranes, MEMS (Micro Electro Mechanical Systems) technology, or the principle of centrifugation to separate plasma or serum from the blood. Plasma or serum samples that are not subjected to concentration measurement immediately after plasma or serum collection are frozen and stored at -80°C until the concentration value is measured. When measuring the concentration value, molecules such as enzymes and aptamers that react with or bind to the target blood substance are used to analyze the concentration value by quantifying substances that increase or decrease due to substrate recognition or spectroscopic values.

[0041] Next, the pharmacological action of the immune checkpoint inhibitor in the evaluation subject is evaluated (predicted) using the concentration value included in the concentration data acquired in step S11 (step S12). Note that before executing step S12, data such as missing values ​​and outliers may be removed from the concentration data acquired in step S11. Here, "evaluating the pharmacological action of the immune checkpoint inhibitor in the evaluation subject" means, for example, evaluating the pharmacological action of the immune checkpoint inhibitor appearing in the evaluation subject. In addition, in step S12, when both the concentration data before the start of treatment and the concentration data after the start of treatment are used, for example, the ratio or difference between the concentration value before the start of treatment and the concentration value after the start of treatment may be calculated, and the evaluation may be performed using the calculated ratio or difference value. In addition, in step S12, the effect of the treatment by the immune checkpoint inhibitor in the evaluation subject (prognosis of the treatment) may be evaluated using the concentration value included in the concentration data before the start of treatment and / or the concentration data after the start of treatment. In addition, in step S12, the risk of occurrence of side effects due to the treatment by the immune checkpoint inhibitor in the evaluation subject may be evaluated using the concentration value included in the concentration data before the start of treatment.

[0042] As described above, in the first embodiment, in step S11, concentration data of the evaluation subject is acquired, and in step S12, the concentration value included in the concentration data of the evaluation subject acquired in step S11 is used to evaluate the pharmacological action of the immune checkpoint inhibitor in the evaluation subject (in other words, information for evaluating the pharmacological action of the immune checkpoint inhibitor in the evaluation subject is acquired). This makes it possible to provide reliable information that can be used as a reference for knowing individual differences in the pharmacological action of the immune checkpoint inhibitor. In particular, when only concentration data before the start of treatment is used in step S12, the evaluation result obtained in this embodiment can be used as reference information when deciding on a treatment method. In addition, when concentration data after the start of treatment or after treatment is used in step S12, the evaluation result obtained in this embodiment can be used to determine whether to continue treatment with the immune checkpoint inhibitor, or can be used as reference information when deciding on a further treatment method.

[0043] In addition, the concentration value (which may be the above-mentioned ratio or difference value) of at least one metabolite among the 21 types of amino acids and 15 types of amino acid-related metabolites may be determined to reflect the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated, and further, the concentration value (which may be the above-mentioned ratio or difference value) may be converted, for example, by the method listed below, and the converted value may be determined to reflect the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated. In other words, the concentration value or the converted value itself may be treated as an evaluation result regarding the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated. In order to ensure that the possible range of concentration values ​​falls within a predetermined range (e.g., the range from 0.0 to 1.0, the range from 0.0 to 10.0, the range from 0.0 to 100.0, or the range from -10.0 to 10.0, etc.), the concentration values ​​may be converted, for example, by adding, subtracting, multiplying, or dividing an arbitrary value to the concentration values, by converting the concentration values ​​using a predetermined conversion method (e.g., exponential transformation, logarithmic transformation, angular transformation, square root transformation, probit transformation, reciprocal transformation, Box-Cox transformation, or power transformation, etc.), or by performing a combination of these calculations on the concentration values. For example, the value of an exponential function with the concentration value as the exponent and Napier's number as the base (specifically, the value of p / (1-p) when the natural logarithm ln(p / (1-p)) of the probability p of a poor prognosis of treatment with an immune checkpoint inhibitor or a high risk of side effects due to the treatment is equal to the concentration value) may be further calculated, and a value obtained by dividing the calculated exponential function value by the sum of 1 and the value (specifically, the value of the probability p) may be further calculated. The concentration values ​​may also be converted so that the converted values ​​under specific conditions are specific values, for example, the concentration values ​​may be converted so that the converted value is 5.0 when the specificity is 80% and the converted value is 8.0 when the specificity is 95%. In addition, for each amino acid and each amino acid-related metabolite, the concentration distribution may be normalized, and then the deviation values ​​may be calculated so that the average is 50 and the standard deviation is 10. These conversions may be performed according to gender or age. In this specification, the density value may be the density value itself, or may be a value obtained by converting the density value.

[0044] In addition, position information regarding the position of a predetermined mark on a predetermined ruler that is visibly displayed on a display device such as a monitor or a physical medium such as paper may be generated using the concentration value (which may be the above-mentioned ratio or difference value) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites, or the converted value if the concentration value is converted, and it may be determined that the generated position information reflects the pharmacological action of the immune checkpoint inhibitor in the evaluation subject. Note that the predetermined ruler is for evaluating the pharmacological action of the immune checkpoint inhibitor in the evaluation subject, and is, for example, a ruler with a scale, which is at least a scale corresponding to the upper and lower limits in the "range in which the concentration value or the converted value can be taken, or a part of the range". In addition, the predetermined mark corresponds to the concentration value or the converted value, and is, for example, a circle or a star.

[0045] In addition, the pharmacological action of the immune checkpoint inhibitor in the subject may be evaluated when the concentration value (which may be the above-mentioned ratio or difference value) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites is lower than or equal to a predetermined value (such as the mean value ± 1SD, 2SD, 3SD, N quantile, N percentile, or a cutoff value recognized for clinical significance) or is equal to or higher than a predetermined value. In this case, instead of the concentration value itself, a concentration deviation value (a value obtained by normalizing the concentration distribution for each amino acid and each amino acid-related metabolite by sex and then deviating the distribution to a mean of 50 and a standard deviation of 10) may be used. For example, the pharmacological action of the immune checkpoint inhibitor in the subject may be evaluated when the concentration deviation value is less than the mean value -2SD (when the concentration deviation value is <30) or when the concentration deviation value is higher than the mean value +2SD (when the concentration deviation value is >70).

[0046] In addition, the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated may be determined by calculating the value of an equation using an equation including a concentration value (which may be the ratio or difference value described above) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites and a variable into which the concentration value (which may be the ratio or difference value described above) is substituted.

[0047] In addition, the calculated value of the formula may be determined to reflect the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated, and the value of the formula may be converted, for example, by the methods listed below, and the converted value may be determined to reflect the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated. In other words, the value of the formula or the converted value itself may be treated as an evaluation result regarding the pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated. In order to ensure that the possible range of the value of the formula falls within a predetermined range (e.g., a range of 0.0 to 1.0, a range of 0.0 to 10.0, a range of 0.0 to 100.0, or a range of -10.0 to 10.0, etc.), the value of the formula may be transformed, for example, by adding, subtracting, multiplying, or dividing an arbitrary value to the value of the formula, by transforming the value of the formula using a predetermined transformation method (e.g., exponential transformation, logarithmic transformation, angular transformation, square root transformation, probit transformation, reciprocal transformation, Box-Cox transformation, or power transformation, etc.), or by performing a combination of these calculations on the value of the formula. For example, the value of an exponential function with the value of the formula as the exponent and Napier's number as the base (specifically, the value of p / (1-p) when the natural logarithm ln(p / (1-p)) of the probability p of a poor prognosis for treatment with an immune checkpoint inhibitor or a high risk of side effects due to the treatment is equal to the value of the formula) may be further calculated, and a value obtained by dividing the calculated exponential function value by the sum of 1 and the value (specifically, the value of probability p) may be further calculated. The value of the formula may also be converted so that the converted value under a particular condition is a particular value, for example, the converted value may be 5.0 when the specificity is 80% and 8.0 when the specificity is 95%. The formula values ​​may also be converted to standard deviation values ​​with an average of 50 and a standard deviation of 10. These conversions may be performed according to gender or age. In this specification, the value of an expression may be the value of the expression itself, or may be a value obtained after the value of the expression is converted.

[0048] In addition, position information regarding the position of a predetermined mark on a predetermined ruler that is visibly displayed on a display device such as a monitor or a physical medium such as paper may be generated using the value of the formula or, if the value of the formula is converted, the converted value, and it may be determined that the generated position information reflects the pharmacological action of the immune checkpoint inhibitor in the evaluation subject. The predetermined ruler is for evaluating the pharmacological action of the immune checkpoint inhibitor in the evaluation subject, and is, for example, a ruler with a scale, which at least shows scales corresponding to the upper and lower limits in the "range in which the value of the formula or the converted value can be taken, or a part of the range". The predetermined mark corresponds to the value of the formula or the converted value, and is, for example, a circle or a star.

[0049] The pharmacological action of the immune checkpoint inhibitor in the subject to be evaluated may be qualitatively evaluated. Specifically, the subject to be evaluated may be classified into one of a plurality of categories defined by at least considering the prognosis of the treatment with the immune checkpoint inhibitor or the risk of side effects due to the treatment, using "the concentration value (which may be the above-mentioned ratio or difference value) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites and one or more preset thresholds" or "the concentration value (which may be the above-mentioned ratio or difference value) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites, an equation including a variable into which the concentration value (which may be the above-mentioned ratio or difference value) is substituted, and one or more preset thresholds." The plurality of categories may include a category for classifying subjects whose prognosis of the treatment is poor or whose risk of side effects due to the treatment is high, a category for classifying subjects whose prognosis of the treatment is good or whose risk of side effects due to the treatment is low, and a category for classifying subjects whose prognosis of the treatment is intermediate between poor and good or whose risk of side effects due to the treatment is moderate. The multiple categories may include a category for subjects with a poor prognosis or a high risk of side effects from the treatment, and a category for subjects with a good prognosis or a low risk of side effects from the treatment. The concentration value (which may be the above-mentioned ratio or difference value) or the value of the formula may be converted by a predetermined method, and the evaluation subject may be classified into one of the multiple categories using the converted value.

[0050] The formula used for the evaluation can be in any format, but may be, for example, in the format shown below. Linear models such as multiple regression equations based on the least squares method, linear discriminants, principal component analysis, and canonical discriminant analysis Generalized linear models such as maximum likelihood logistic regression and Cox regression -Generalized linear mixed model that considers random effects such as individual differences and facility differences in addition to generalized linear models · Formulas created by cluster analysis such as K-means and hierarchical cluster analysis Formulas based on Bayesian statistics such as MCMC (Markov Chain Monte Carlo), Bayesian Networks, and Hierarchical Bayesian methods - Formulas created by class classification such as support vector machines and decision trees Formulas created using methods that do not fall into the above categories, such as fractional formulas An equation that can be expressed as a sum of different forms of equations

[0051] Furthermore, the formula used in the evaluation may be prepared, for example, by the method described in International Publication No. WO 2004 / 052191, an international application filed by the present applicant, or the method described in International Publication No. WO 2006 / 098192, an international application filed by the present applicant. Note that, if the formula is obtained by these methods, the formula can be suitably used to evaluate the pharmacological action of an immune checkpoint inhibitor, regardless of the unit of the concentration value of the amino acid or amino acid-related metabolite in the concentration data as input data.

[0052] Here, in the multiple regression equation, multiple logistic regression equation, canonical discriminant function, etc., a coefficient and a constant term are added to each variable, and these coefficients and constant terms may be preferably real numbers, more preferably values ​​within the range of the 99% confidence interval of the coefficients and constant terms obtained for performing the various classifications from the data, and even more preferably values ​​within the range of the 95% confidence interval of the coefficients and constant terms obtained for performing the various classifications from the data. In addition, the value of each coefficient and its confidence interval may be multiplied by a real number, and the value of the constant term and its confidence interval may be added, subtracted, multiplied, or divided by an arbitrary real constant. When a logistic regression equation, a linear discriminant, a multiple regression equation, etc. are used for evaluation, linear transformation (addition of a constant, constant multiplication) and monotonically increasing (decreasing) transformation (for example, logit transformation, etc.) do not change the evaluation performance and are equivalent to the one before the transformation, so that the one after these transformations may be used for evaluation.

[0053] A fractional expression is one in which the numerator is expressed as the sum of the variables A, B, C, ... and / or the denominator is expressed as the sum of the variables a, b, c, .... Fractional expressions also include sums of fractional expressions of this type, α, β, γ, ... (such as α + β). Fractional expressions also include divided fractional expressions. The variables used in the numerator and denominator may each have an appropriate coefficient. The variables used in the numerator and denominator may also be duplicated. Each fractional expression may have an appropriate coefficient. The values ​​of the coefficients of each variable and the values ​​of the constant terms may be real numbers. In addition, although the positive / negative sign of the correlation with the objective variable is generally reversed between a fractional formula and one in which the numerator variable and denominator variable have been swapped, the correlation is maintained and the evaluation performance can be considered to be equivalent, so fractional formulas also include those in which the numerator variable and denominator variable have been swapped.

[0054] When evaluating the pharmacological action of an immune checkpoint inhibitor, values ​​related to other biological information (e.g., values ​​listed below) may be used in addition to the concentration values ​​of at least one metabolite among the 21 amino acids and the 15 amino acid-related metabolites. Furthermore, the formula used in the evaluation may further include one or more variables into which values ​​related to other biological states (e.g., values ​​listed below) are substituted, in addition to the variables into which the concentration values ​​of at least one metabolite among the 21 amino acids and the 15 amino acid-related metabolites are substituted. 1. Concentrations of blood metabolites (sugars, lipids, etc.) other than amino acids and amino acid-related metabolites, proteins, peptides, minerals, hormones, etc. 2. Blood test values ​​such as tumor markers, albumin, total protein, triglycerides (neutral fats), HbA1c, LDL cholesterol, HDL cholesterol, amylase, total bilirubin, and uric acid 3. Immune-related test values ​​such as blood cytokines, immune cell counts, immune cell cytokines, and delayed type hyperresponsiveness (DTH) 4. Values ​​obtained from imaging information such as ultrasound echo, upper and lower endoscopy, X-ray, CT, and MRI 5. Values ​​related to biomarkers such as age, height, weight, BMI, blood pressure, sex, smoking information, dietary information, drinking information, exercise information, stress information, sleep information, family medical history, and disease history (diabetes, pancreatitis, etc.) 6. Values ​​obtained from multi-omics analysis information, information on cancer gene mutations, information on microsatellite instability, information on cancer-derived antigens and antibodies, or information on molecular expression of PD-1, PD-L1, etc.

[0055] [Second embodiment] [2-1. Overview of the second embodiment] Here, an overview of the second embodiment will be described with reference to FIG. 2. FIG. 2 is a principle configuration diagram showing the basic principle of the second embodiment. In the description of the second embodiment, explanations that overlap with the above-mentioned first embodiment may be omitted. In particular, a case in which the value of the formula or a value after conversion thereof is used when evaluating the pharmacological action of an immune checkpoint inhibitor is described here as an example, but for example, a concentration value, a ratio of concentration values, or a difference in concentration values, or a value after conversion thereof (for example, a concentration deviation value, etc.) may also be used.

[0056] The control unit evaluates the pharmacological action of the immune checkpoint inhibitor in the evaluation subject by calculating the value of the formula using a formula stored in advance in the storage unit that includes the concentration value contained in the previously acquired concentration data regarding the concentration value of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in the blood of the evaluation subject (for example, an individual such as an animal or human) that may be the subject of treatment with the immune checkpoint inhibitor, and a variable into which the concentration value is substituted (step S21). In addition, when both the concentration data before the start of treatment and the concentration data after the start of treatment are used in step S21, the control unit may, for example, calculate the ratio or difference between the concentration value before the start of treatment and the concentration value after the start of treatment, and substitute the calculated ratio or difference value for the variable to calculate the value of the formula. This makes it possible to provide highly reliable information that can be used as a reference for knowing the individual differences in the pharmacological action of the immune checkpoint inhibitor.

[0057] The formula used in step S21 may be one created based on the formula creation process (steps 1 to 4) described below. Here, an overview of the formula creation process will be described. Note that the process described here is merely an example, and the formula creation method is not limited to this.

[0058] First, the control unit creates a candidate formula (e.g., y=a1x1+a2x2+···+anxn, y: index data, xi: concentration data, ai: constant, i=1,2,···,n) based on a predetermined formula creation method from index state information (which may be data from which missing values ​​and outliers have been removed in advance) previously stored in the storage unit (step 1). The index state information includes concentration data (e.g., concentration data of amino acids and amino acid-related metabolites before the start of treatment, concentration data of amino acids and amino acid-related metabolites after the start of treatment, or concentration data on the change in amino acids and amino acid-related metabolites before and after the start of treatment, etc.) and index data on the prognosis of treatment with an immune checkpoint inhibitor or the risk of side effects due to the treatment (e.g., binary data on poor / good prognosis, or binary data on the presence or absence of side effects, etc.).

[0059] In step 1, multiple candidate formulas may be created from the index state information by using multiple different formula creation methods (including those related to multivariate analysis such as principal component analysis, discriminant analysis, support vector machine, multiple regression analysis, Cox regression analysis, logistic regression analysis, k-means method, cluster analysis, and decision tree). Specifically, multiple groups of candidate formulas may be created simultaneously in parallel using multiple different algorithms for index state information, which is multivariate data consisting of concentration data and index data obtained by analyzing blood obtained before and / or after the start of treatment from a large number of patients who may be the target of immune checkpoint inhibitor treatment. For example, discriminant analysis and logistic regression analysis may be performed simultaneously using different algorithms to create two different candidate formulas. In addition, the candidate formula created by performing principal component analysis may be used to convert the index state information, and discriminant analysis may be performed on the converted index state information to create a candidate formula. This ultimately allows the creation of a formula optimal for evaluation.

[0060] Here, the candidate formula created using principal component analysis is a linear formula including each variable that maximizes the variance of all concentration data. Also, the candidate formula created using discriminant analysis is a higher-order formula (including exponential and logarithmic) including each variable that minimizes the ratio of the sum of variances in each group to the variance of all concentration data. Also, the candidate formula created using support vector machine is a higher-order formula (including kernel function) including each variable that maximizes the boundary between groups. Also, the candidate formula created using multiple regression analysis is a higher-order formula including each variable that minimizes the sum of distances from all concentration data. Also, the candidate formula created using Cox regression analysis is a linear model including a log hazard ratio, and is a linear formula including each variable and its coefficient that maximizes the likelihood of the model. Also, the candidate formula created using logistic regression analysis is a linear model that represents the log odds of probability, and is a linear formula including each variable that maximizes the likelihood of the probability. The k-means method is a method that searches k neighbors of each concentration data, defines the group to which the most neighboring points belong as the group to which the data belongs, and selects the variable that best matches the defined group to which the input concentration data belongs. Cluster analysis is a method of clustering (grouping) points that are closest to each other among all concentration data. A decision tree is a method of ranking variables and determining the group of concentration data from the possible patterns of the variables with higher rankings.

[0061] Returning to the explanation of the formula creation process, the control unit verifies (cross-validates) the candidate formulas created in step 1 based on a predetermined verification method (step 2). The verification of the candidate formulas is performed for each candidate formula created in step 1. In step 2, at least one of the discrimination rate, sensitivity, specificity, information criterion (Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC)), ROC_AUC (area under the receiver characteristic curve), C-index (Concordance index), etc. of the candidate formula may be verified based on at least one of the bootstrap method, hold-out method, N-fold method, leave-one-out method, etc. This makes it possible to create a candidate formula with high predictability or robustness that takes into account index state information and evaluation conditions.

[0062] Here, the discrimination rate is the rate at which the evaluation method according to the present embodiment correctly evaluates evaluation targets whose true state is negative (e.g., evaluation targets whose treatment prognosis is good or no side effects) as negative, and correctly evaluates evaluation targets whose true state is positive (e.g., evaluation targets whose treatment prognosis is poor or side effects have occurred) as positive. The sensitivity is the rate at which the evaluation method according to the present embodiment correctly evaluates evaluation targets whose true state is positive as positive. The specificity is the rate at which the evaluation method according to the present embodiment correctly evaluates evaluation targets whose true state is negative as negative. The Akaike Information Criterion (AIC) is a criterion that indicates the degree to which observed data matches a statistical model in the case of regression analysis, etc., and the model with the smallest value defined by "-2 x (maximum logarithmic likelihood of statistical model) + 2 x (number of free parameters of statistical model)" is judged to be the best. The Bayesian Information Criterion (BIC) is a model selection criterion derived based on the idea of ​​Bayesian statistics, and judges the model with the smallest value defined by "-2 × (maximum log likelihood of statistical model) + (number of free parameters of statistical model) × ln (sample size)" (model with few parameters) to be the best. The ROC_AUC is defined as the area under the receiver characteristic curve (ROC), which is a curve created by plotting (x, y) = (1 - specificity, sensitivity) on a two-dimensional coordinate system. The ROC_AUC value is 1 for perfect discrimination, and the closer this value is to 1, the higher the discrimination. The C-index is an index that indicates the accuracy of prognosis prediction proposed by Harrell et al., and is a nonparametric index that indicates the degree to which the magnitude relationship between the event occurrence probability predicted by the model and the actual event occurrence probability matches. Predictability is the average of the discrimination rate, sensitivity, and specificity obtained by repeatedly verifying the candidate formula. Robustness is the variance of the discrimination rate, sensitivity, and specificity obtained by repeatedly verifying the candidate formula.

[0063] Returning to the explanation of the formula creation process, the control unit selects a combination of concentration data included in the index state information used when creating the candidate formula by selecting variables of the candidate formula based on a predetermined variable selection method (step 3). In step 3, variable selection may be performed for each candidate formula created in step 1. This allows the variables of the candidate formula to be appropriately selected. Then, step 1 is executed again using the index state information including the concentration data selected in step 3. In step 3, the variables of the candidate formula may be selected based on at least one of the stepwise method, the best path method, the neighborhood search method, and the genetic algorithm from the verification result in step 2. In addition, the best path method is a method of selecting variables by sequentially reducing the variables included in the candidate formula one by one and optimizing the evaluation index given by the candidate formula.

[0064] Returning to the explanation of the formula creation process, the control unit repeatedly executes the above-mentioned steps 1, 2, and 3, and creates a formula to be used in evaluation by selecting a candidate formula to be used in evaluation from among multiple candidate formulas based on the verification results accumulated thereby (step 4). Note that the selection of the candidate formula may involve, for example, selecting the optimal one from among candidate formulas created using the same formula creation method, or selecting the optimal one from among all candidate formulas.

[0065] As described above, in the formula creation process, the processes related to the creation of candidate formulas, the verification of the candidate formulas, and the selection of variables for the candidate formulas are systematized (systemized) in a series of flows based on the index state information, and executed to create a formula optimal for evaluating the pharmacological action of immune checkpoint inhibitors. In other words, in the formula creation process, the concentration values ​​of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites are used in multivariate statistical analysis, and a formula with high evaluation performance is extracted by combining a variable selection method and cross-validation to select an optimal and robust set of variables.

[0066] [2-2. Configuration of the second embodiment] Here, the configuration of the evaluation system according to the second embodiment (hereinafter, sometimes referred to as this system) will be described with reference to Figs. 3 to 13. Note that this system is merely an example, and the present invention is not limited thereto. In particular, here, a case where the value of the formula or a value after conversion thereof is used when evaluating the pharmacological action of an immune checkpoint inhibitor is described as an example, but for example, a concentration value, a ratio of concentration values, or a difference in concentration values, or a value after conversion thereof (for example, a concentration deviation value, etc.) may also be used.

[0067] First, the overall configuration of the present system will be described with reference to Fig. 3 and Fig. 4. Fig. 3 is a diagram showing an example of the overall configuration of the present system. Fig. 4 is a diagram showing another example of the overall configuration of the present system. As shown in Fig. 3, the present system is configured by communicatively connecting an evaluation device 100 that evaluates the pharmacological action of an immune checkpoint inhibitor in an individual to be evaluated, and a client device 200 (corresponding to a terminal device of the present invention) that provides individual concentration data regarding the concentration value of at least one metabolite of the 21 types of amino acids and the 15 types of amino acid-related metabolites in blood via a network 300.

[0068] In this system, the client device 200 that is the source of data used in the evaluation and the client device 200 that is the destination of the evaluation results may be separate devices. As shown in Fig. 4, in addition to the evaluation device 100 and the client device 200, the system may be configured by connecting a database device 400 that stores index state information used when creating a formula in the evaluation device 100 and formulas used in the evaluation, etc., via a network 300 so as to be able to communicate with each other.

[0069] Next, the configuration of the evaluation device 100 of this system will be described with reference to Fig. 5 to Fig. 11. Fig. 5 is a block diagram showing an example of the configuration of the evaluation device 100 of this system, and conceptually shows only the parts of the configuration that are related to the present invention.

[0070] The evaluation device 100 is composed of a control unit 102 such as a CPU (Central Processing Unit) that controls the evaluation device in an integrated manner, a communication interface unit 104 that communicatively connects the evaluation device to a network 300 via a communication device such as a router and a wired or wireless communication line such as a dedicated line, a storage unit 106 that stores various databases, tables, files, etc., and an input / output interface unit 108 that connects to an input device 112 and an output device 114, and these units are communicatively connected via any communication path. Here, the evaluation device 100 may be composed in the same housing as various analyzers (e.g., amino acid and amino acid-related metabolite analyzers, etc.). For example, a small analyzer having a configuration (hardware and software) that calculates (measures) the concentration value of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites in blood and outputs the calculated value (printing, displaying on a monitor, etc.), further comprising an evaluation unit 102d described later, and the result obtained by the evaluation unit 102d is output using the configuration.

[0071] The communication interface unit 104 mediates communication between the evaluation device 100 and the network 300 (or a communication device such as a router). That is, the communication interface unit 104 has a function of communicating data with other terminals via a communication line.

[0072] The input / output interface unit 108 is connected to an input device 112 and an output device 114. Here, the output device 114 may be a monitor (including a home television), a speaker, or a printer (hereinafter, the output device 114 may be referred to as a monitor 114). The input device 112 may be a keyboard, a mouse, a microphone, or a monitor that cooperates with a mouse to realize a pointing device function.

[0073] The memory unit 106 is a storage means, and may be, for example, a memory device such as a RAM (Random Access Memory) or a ROM (Read Only Memory), a fixed disk device such as a hard disk, a flexible disk, an optical disk, etc. The memory unit 106 records computer programs for cooperating with an OS (Operating System) to give instructions to a CPU to perform various processes. As shown in the figure, the memory unit 106 stores a concentration data file 106a, an index state information file 106b, a specified index state information file 106c, a formula related information database 106d, and an evaluation result file 106e.

[0074] The concentration data file 106a stores concentration data (for example, either or both of concentration data before the start of treatment and concentration data after the start of treatment) on the concentration value of at least one metabolite among the 21 kinds of amino acids and the 15 kinds of amino acid-related metabolites in blood. FIG. 6 is a diagram showing an example of information stored in the concentration data file 106a. As shown in FIG. 6, the information stored in the concentration data file 106a is configured by correlating individual numbers for uniquely identifying individuals (samples) to be evaluated with concentration data. Here, in FIG. 6, the concentration data is treated as a numerical value, i.e., a continuous scale, but the concentration data may be a nominal scale or an ordinal scale. In the case of a nominal scale or an ordinal scale, an arbitrary numerical value may be assigned to each state for analysis. In addition, the concentration data may be combined with values ​​related to other biological information (see above).

[0075] Returning to FIG. 5, the index state information file 106b stores the index state information used when creating the formula. FIG. 7 is a diagram showing an example of information stored in the index state information file 106b. As shown in FIG. 7, the information stored in the index state information file 106b is configured by mutually associating an individual number, index data related to the prognosis of treatment with an immune checkpoint inhibitor or the risk of side effects caused by the treatment, and concentration data. Here, in FIG. 7, the index data and concentration data are treated as numerical values ​​(i.e., continuous scale), but the index data and concentration data may be nominal or ordinal scales. In the case of nominal or ordinal scales, analysis may be performed by assigning arbitrary numerical values ​​to each state.

[0076] Returning to Fig. 5, the specified index status information file 106c stores index status information specified by the specification unit 102b, which will be described later. Fig. 8 is a diagram showing an example of information stored in the specified index status information file 106c. As shown in Fig. 8, the information stored in the specified index status information file 106c is configured by associating individual numbers, specified index data, and specified concentration data with each other.

[0077] Returning to Fig. 5, the formula-related information database 106d is composed of a formula file 106d1 that stores formulas created by the formula creation unit 102c described later. The formula file 106d1 stores formulas used in evaluation. Fig. 9 is a diagram showing an example of information stored in the formula file 106d1. As shown in Fig. 9, the information stored in the formula file 106d1 is composed of ranks, formulas (Fp(His,...), Fp(His,hKyn,Kyn), Fk(His,hKyn,Kyn,...), etc. in Fig. 9), thresholds corresponding to each formula creation method, and verification results of each formula (for example, the value of each formula) that are mutually associated with each other.

[0078] Returning to Fig. 5, the evaluation result file 106e stores the evaluation results obtained by the evaluation unit 102d described later. Fig. 10 is a diagram showing an example of information stored in the evaluation result file 106e. The information stored in the evaluation result file 106e is configured by associating an individual number for uniquely identifying an individual (sample) to be evaluated, individual concentration data acquired in advance, and an evaluation result regarding the pharmacological action (treatment prognosis or risk of side effects) of the immune checkpoint inhibitor (for example, the value of a formula calculated by a calculation unit 102d1 described later, the value after converting the value of the formula by a conversion unit 102d2 described later, position information generated by a generation unit 102d3 described later, or a classification result obtained by a classification unit 102d4 described later, etc.).

[0079] Returning to Fig. 5, the control unit 102 has an internal memory for storing control programs such as an OS, programs that define various processing procedures, and required data, and executes various information processing based on these programs. As shown in the figure, the control unit 102 is roughly divided into an acquisition unit 102a, a designation unit 102b, a formula creation unit 102c, an evaluation unit 102d, a result output unit 102e, and a transmission unit 102f. The control unit 102 also performs data processing such as removal of data with missing values, removal of data with many outliers, and removal of variables with many data with missing values ​​for the index state information transmitted from the database device 400 and the concentration data transmitted from the client device 200.

[0080] The acquiring unit 102a acquires information (specifically, concentration data, index state information, formula, etc.). For example, the acquiring unit 102a may acquire information by receiving information (specifically, concentration data, index state information, formula, etc.) transmitted from the client device 200 or the database device 400 via the network 300, etc. The acquiring unit 102a may receive data used for evaluation transmitted from a client device 200 different from the client device 200 to which the evaluation result is transmitted. For example, when the evaluation device 100 includes a mechanism (including hardware and software) for reading information recorded on a recording medium, the acquiring unit 102a may acquire information by reading information (specifically, concentration data, index state information, formula, etc.) recorded on the recording medium via the mechanism. The designating unit 102b designates the index data and concentration data to be used for creating the formula.

[0081] The equation creation unit 102c creates an equation based on the index state information acquired by the acquisition unit 102a and the index state information designated by the designation unit 102b. When the equation is stored in advance in a predetermined storage area of ​​the storage unit 106, the equation creation unit 102c may create an equation by selecting a desired equation from the storage unit 106. The equation creation unit 102c may also create an equation by selecting a desired equation from another computer device (e.g., database device 400) that has equations stored in advance and downloading the equation.

[0082] The evaluation unit 102d evaluates the pharmacological action of the immune checkpoint inhibitor in an individual by calculating the value of the formula using a formula obtained in advance (for example, a formula created by the formula creation unit 102c or a formula acquired by the acquisition unit 102a) and a concentration value included in the individual's concentration data acquired by the acquisition unit 102a. The evaluation unit 102d may evaluate the pharmacological action of the immune checkpoint inhibitor in an individual by using a concentration value, a ratio of concentration values, or a difference in concentration values, or a value converted from these (for example, a concentration deviation value) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites.

[0083] Here, the configuration of the evaluation unit 102d will be described with reference to Fig. 11. Fig. 11 is a block diagram showing the configuration of the evaluation unit 102d, and conceptually shows only the parts of the configuration related to the present invention. The evaluation unit 102d further includes a calculation unit 102d1, a conversion unit 102d2, a generation unit 102d3, and a classification unit 102d4.

[0084] The calculation unit 102d1 calculates the value of the formula using a formula including at least a concentration value (which may be the above-mentioned ratio or difference value) of at least one metabolite among the 21 types of amino acids and the 15 types of amino acid-related metabolites and a variable into which the concentration value is substituted. The evaluation unit 102d may store the value of the formula calculated by the calculation unit 102d1 as the evaluation result in a predetermined storage area of ​​the evaluation result file 106e.

[0085] The conversion unit 102d2 converts the value of the formula calculated by the calculation unit 102d1, for example, using the conversion method described above. The evaluation unit 102d may store the value converted by the conversion unit 102d2 in a predetermined storage area of ​​the evaluation result file 106e as the evaluation result. The conversion unit 102d2 may also convert the concentration value included in the concentration data or the ratio or difference of the concentration values, for example, using the conversion method described above.

[0086] The generating unit 102d3 generates position information on the position of a predetermined mark on a predetermined ruler that is visibly shown on a display device such as a monitor or a physical medium such as paper, using the value of the formula calculated by the calculating unit 102d1 or the value after conversion by the converting unit 102d2 (which may be a concentration value, a ratio of concentration values, a difference of concentration values, or a value after conversion of these). Note that the evaluating unit 102d may store the position information generated by the generating unit 102d3 in a predetermined storage area of ​​the evaluation result file 106e as an evaluation result.

[0087] The classification unit 102d4 uses the value of the formula calculated by the calculation unit 102d1 or the value converted by the conversion unit 102d2 (which may be a concentration value, a ratio of concentration values, a difference in concentration values, or a value after these conversions) to classify an individual into one of a plurality of categories defined taking into consideration at least the prognosis of treatment with an immune checkpoint inhibitor or the risk of side effects due to the treatment.

[0088] The result output unit 102e outputs to the output device 114 the processing results of each processing unit in the control unit 102 (including the evaluation result obtained by the evaluation unit 102d) and the like.

[0089] The transmission unit 102f transmits the evaluation result to the client device 200 that transmitted the concentration data of the individual, and transmits the formula created by the evaluation device 100 and the evaluation result to the database device 400. The transmission unit 102f may transmit the evaluation result to a client device 200 different from the client device 200 that transmitted the data used for the evaluation.

[0090] Next, the configuration of client device 200 of this system will be described with reference to Fig. 12. Fig. 12 is a block diagram showing an example of the configuration of client device 200 of this system, and conceptually shows only the parts of the configuration that are related to the present invention.

[0091] The client device 200 is composed of a control unit 210, a ROM 220, a HD (Hard Disk) 230, a RAM 240, an input device 250, an output device 260, an input / output IF 270, and a communication IF 280, and these units are communicably connected via any communication path. The client device 200 may be based on an information processing device (for example, a known information processing terminal such as a personal computer, a workstation, a home game device, an Internet TV, a PHS (Personal Handyphone System) terminal, a mobile terminal, a mobile communication terminal, a PDA (Personal Digital Assistant), etc.) to which peripheral devices such as a printer, a monitor, an image scanner, etc. are connected as necessary.

[0092] The input device 250 is a keyboard, a mouse, a microphone, etc. A monitor 261, which will be described later, also realizes a pointing device function in cooperation with a mouse. The output device 260 is an output means for outputting information received via the communication IF 280, and includes a monitor (including a home television) 261 and a printer 262. In addition, the output device 260 may be provided with a speaker, etc. The input / output IF 270 is connected to the input device 250 and the output device 260.

[0093] The communication IF 280 communicatively connects the client device 200 and the network 300 (or a communication device such as a router). In other words, the client device 200 is connected to the network 300 via a communication device such as a modem, a TA (Terminal Adapter), or a router and a telephone line, or via a dedicated line. This allows the client device 200 to access the evaluation device 100 in accordance with a predetermined communication protocol.

[0094] The control unit 210 includes a receiving unit 211 and a transmitting unit 212. The receiving unit 211 receives various information such as the evaluation result transmitted from the evaluation device 100 via the communication IF 280. The transmitting unit 212 transmits various information such as the concentration data of the individual to the evaluation device 100 via the communication IF 280.

[0095] The control unit 210 may realize all or any part of the processing performed by the control unit with a CPU and a program that is interpreted and executed by the CPU. A computer program for giving instructions to the CPU in cooperation with the OS and performing various processing is recorded in the ROM 220 or the HD 230. The computer program is executed by being loaded into the RAM 240, and constitutes the control unit 210 in cooperation with the CPU. The computer program may also be recorded in an application program server connected to the client device 200 via any network, and the client device 200 may download all or any part of the computer program as necessary. Also, all or any part of the processing performed by the control unit 210 may be realized by hardware such as wired logic.

[0096] Here, the control unit 210 may include an evaluation unit 210a (including a calculation unit 210a1, a conversion unit 210a2, a generation unit 210a3, and a classification unit 210a4) having the same functions as those of the evaluation unit 102d included in the evaluation device 100. When the control unit 210 includes the evaluation unit 210a, the evaluation unit 210a may convert the value of the formula (which may be a concentration value, a ratio of concentration values, or a difference in concentration values) in the conversion unit 210a2, generate position information corresponding to the value of the formula or the converted value (which may be a concentration value, a ratio of concentration values, a difference in concentration values, or a value after conversion thereof) in the generation unit 210a3, or classify the individual into one of a plurality of categories using the value of the formula or the converted value (which may be a concentration value, a ratio of concentration values, a difference in concentration values, or a value after conversion thereof) in the classification unit 210a4, depending on the information included in the evaluation result transmitted from the evaluation device 100.

[0097] Next, the network 300 of this system will be described with reference to Figures 3 and 4. The network 300 has a function of connecting the evaluation device 100, the client device 200, and the database device 400 so that they can communicate with each other, and is, for example, the Internet, an intranet, or a LAN (Local Area Network) (including both wired and wireless networks). In addition, network 300 may be a VAN (Value-Added Network), a personal computer communication network, a public telephone network (including both analog and digital), a leased line network (including both analog and digital), a CATV (Community Antenna TeleVision) network, a mobile circuit-switched network or a mobile packet-switched network (including the IMT (International Mobile Telecommunication) 2000 system, the GSM (registered trademark) (Global System for Mobile Communications) system, or the PDC (Personal Digital Cellular) / PDC-P system, etc.), a radio paging network, a local wireless network such as Bluetooth (registered trademark), a PHS network, or a satellite communication network (including CS (Communication Satellite), BS (Broadcasting Satellite), or ISDB (Integrated Services Digital Broadcasting), etc.).

[0098] Next, the configuration of the database device 400 of this system will be described with reference to Fig. 13. Fig. 13 is a block diagram showing an example of the configuration of the database device 400 of this system, and conceptually shows only the parts of the configuration that are related to the present invention.

[0099] The database device 400 has a function of storing index state information used when creating an equation in the evaluation device 100 or the database device itself, an equation created in the evaluation device 100, an evaluation result in the evaluation device 100, etc. As shown in Fig. 13, the database device 400 is composed of a control unit 402 such as a CPU that controls the database device in an overall manner, a communication interface unit 404 that communicatively connects the database device to the network 300 via a communication device such as a router and a wired or wireless communication circuit such as a dedicated line, a storage unit 406 that stores various databases, tables, files (e.g., files for Web pages), etc., and an input / output interface unit 408 that connects to an input device 412 and an output device 414, and these units are communicatively connected via any communication path.

[0100] The memory unit 406 is a storage means, and may be, for example, a memory device such as a RAM or ROM, a fixed disk device such as a hard disk, a flexible disk, an optical disk, or the like. The memory unit 406 stores various programs and the like used for various processes. The communication interface unit 404 mediates communication between the database device 400 and the network 300 (or a communication device such as a router). That is, the communication interface unit 404 has a function of communicating data with other terminals via a communication line. The input / output interface unit 408 is connected to an input device 412 and an output device 414. Here, the output device 414 may be a monitor (including a home television), a speaker, or a printer. The input device 412 may be a keyboard, a mouse, a microphone, or a monitor that cooperates with a mouse to realize a pointing device function.

[0101] The control unit 402 has an internal memory for storing control programs such as an OS, programs defining various processing procedures, required data, etc., and executes various information processing based on these programs. As shown in the figure, the control unit 402 is roughly equipped with a transmission unit 402a and a reception unit 402b. The transmission unit 402a transmits various information such as index state information and equations to the evaluation device 100. The reception unit 402b receives various information such as equations and evaluation results transmitted from the evaluation device 100.

[0102] In this description, an example has been given in which the evaluation device 100 receives concentration data, calculates the value of the formula, classifies the individuals into categories, and transmits the evaluation results, while the client device 200 receives the evaluation results. However, if the client device 200 is equipped with the evaluation unit 210a, it is sufficient for the evaluation device 100 to calculate the value of the formula. For example, the conversion of the value of the formula, the generation of position information, and the classification of the individuals into categories may be appropriately shared between the evaluation device 100 and the client device 200. For example, when the client device 200 receives a value of an equation from the evaluation device 100, the evaluation unit 210a may convert the value of the equation in the conversion unit 210a2, generate position information corresponding to the value of the equation or the converted value in the generation unit 210a3, and classify the individual into one of a plurality of categories using the value of the equation or the converted value in the classification unit 210a4. Furthermore, when the client device 200 receives a converted value from the evaluation device 100, the evaluation unit 210a may generate position information corresponding to the converted value in the generation unit 210a3, or classify the individual into one of a plurality of categories using the converted value in the classification unit 210a4. In addition, when the client device 200 receives the value of the formula or the converted value and location information from the evaluation device 100, the evaluation unit 210a may classify the individual into one of a plurality of categories using the value of the formula or the converted value in the classification unit 210a4.

[0103] [2-3. Other embodiments] The evaluation device, calculation device, evaluation method, calculation program, recording medium, evaluation system, and terminal device according to the present invention may be embodied in various different embodiments within the scope of the technical idea described in the claims, in addition to the second embodiment described above.

[0104] Furthermore, among the processes described in the second embodiment, all or part of the processes described as being performed automatically can be performed manually, or all or part of the processes described as being performed manually can be performed automatically using known methods.

[0105] In addition, the processing procedures, control procedures, specific names, registered data for each process, information including parameters such as search conditions, screen examples, and database configurations shown in the above documents and drawings can be changed as desired unless otherwise specified.

[0106] Moreover, with regard to the evaluation device 100, the components shown in the figures are merely functional concepts, and the evaluation device 100 does not necessarily have to be physically configured as shown in the figures.

[0107] For example, the processing functions of the evaluation device 100, particularly the processing functions performed by the control unit 102, may be realized in whole or in part by a CPU and a program interpreted and executed by the CPU, or may be realized as hardware using wired logic. The program is recorded in a non-transient computer-readable recording medium including programmed instructions for causing an information processing device to execute the evaluation method or calculation method according to the present invention, and is mechanically read by the evaluation device 100 as necessary. That is, a computer program for giving instructions to the CPU in cooperation with the OS and performing various processes is recorded in the storage unit 106 such as a ROM or HDD (Hard Disk Drive). This computer program is executed by being loaded into a RAM, and constitutes a control unit in cooperation with the CPU.

[0108] In addition, this computer program may be stored in an application program server connected to the evaluation device 100 via any network, and it is also possible to download all or part of it as necessary.

[0109] The evaluation program or calculation program according to the present invention may be stored in a non-transitory computer-readable recording medium, or may be configured as a program product. Here, the term "recording medium" includes any "portable physical medium" such as a memory card, a Universal Serial Bus (USB) memory, a Secure Digital (SD) card, a flexible disk, a magneto-optical disk, a ROM, an Erasable Programmable Read Only Memory (EPROM), an Electrically Erasable and Programmable Read Only Memory (EEPROM) (registered trademark), a Compact Disc Read Only Memory (CD-ROM), a Magneto-Optical disk (MO), a Digital Versatile Disk (DVD), and a Blu-ray (registered trademark) Disc.

[0110] Moreover, a "program" is a data processing method written in any language or description method, and may be in any form, such as source code or binary code. Note that a "program" is not necessarily limited to a single configuration, but also includes a distributed configuration as multiple modules or libraries, and a program that works with a separate program, such as an OS, to achieve its function. Note that the specific configuration and reading procedure for reading a recording medium in each device shown in the embodiments, as well as the installation procedure after reading, may use well-known configurations and procedures.

[0111] The various databases etc. stored in the memory unit 106 are storage means such as memory devices such as RAM and ROM, fixed disk devices such as hard disks, flexible disks, and optical disks, and store various programs, tables, databases, and web page files etc. used for various processes and providing websites.

[0112] The evaluation device 100 may be configured as an information processing device such as a known personal computer or a workstation, or may be configured as the information processing device to which any peripheral device is connected. The evaluation device 100 may be realized by installing software (including a program or data) that realizes the evaluation method or calculation method of the present invention in the information processing device.

[0113] Furthermore, the specific form of distribution and integration of the devices is not limited to that shown in the drawings, and all or part of them can be functionally or physically distributed and integrated in any unit according to various additions or functional loads. In other words, the above-mentioned embodiments can be implemented in any combination, or the embodiments can be implemented selectively. EXAMPLES

[0114] An observational clinical study was conducted to analyze the relationship between the measurement of peripheral blood amino acid and metabolite concentrations in patients using immune checkpoint inhibitors and the therapeutic effect. Blood samples were obtained from patients with advanced or recurrent lung cancer scheduled for treatment with immune checkpoint inhibitors, and 21 types of amino acids (Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Trp, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, and Gly) and 15 types of amino acid-related metabolites (AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA) were analyzed. The antibody therapeutic agent used was the anti-PD-1 antibody nivolumab or pembrolizumab.

[0115] Blood samples were collected from a peripheral vein before and 6 weeks after the start of treatment. The blood samples were cooled immediately after collection, and plasma was separated from the blood samples. The concentrations of free amino acids and amino acid-related metabolites in plasma were measured using an LC-MS analyzer or an LC-MS / MS analyzer according to the measurement method (A) described in the above embodiment. Background information on the patients, such as the progression and tissue type of cancer and clinical test values, was collected from the patients. Furthermore, the treatment prognosis (overall survival time) of each patient was tracked for up to two years from the start of treatment (average follow-up period 272 days).

[0116] FIG. 14 shows the changes in blood concentrations of the 21 amino acids and the 15 amino acid-related metabolites before and after the start of treatment.

[0117] Figure 14 shows the average concentration values ​​of each amino acid and each amino acid-related metabolite before the start of treatment (pre) and after 6 weeks of treatment (post). The results of paired t-test showed that hKyn, Kyn and QA were significantly increased after 6 weeks of treatment compared to before the start of treatment (p<0.05).

[0118] In addition, a correlation analysis was performed between the concentration values ​​of the 21 amino acids and the 15 amino acid-related metabolites before the start of treatment and the treatment prognosis (overall survival). The 53 lung cancer patients analyzed suffered from non-small cell lung cancer, and nivolumab was used in 25 cases and pembrolizumab in 28 cases. There were 35 deaths. The analysis results are shown in Figure 15. Figure 15 shows the hazard ratio, P value, and C-Index in the univariate COX hazard analysis of each amino acid and each amino acid-related metabolite and overall survival. Six types of amino acids, His, Thr, Ala, Cit, Arg, and Trp, were identified as significantly changed amino acids, and five types of amino acid-related metabolites, hKyn, hTrp, AnthA, QA, and NP, were identified as significantly changed amino acid-related metabolites. It was found that the blood concentration values ​​of the six amino acids and the five amino acid-related metabolites before the start of treatment, which were significantly correlated with the treatment prognosis, can be an index for predicting the treatment prognosis of immune checkpoint inhibitors.

[0119] In addition, a correlation analysis was performed between the concentration values ​​of the 21 types of amino acids and the 15 types of amino acid-related metabolites 6 weeks after the start of treatment and the treatment prognosis (overall survival). The analysis results are shown in FIG. 16. FIG. 16 shows the hazard ratio, P value, and C-index in the univariate COX hazard analysis of each amino acid and each amino acid-related metabolite and the treatment prognosis (overall survival). Ten types of amino acids, His, Thr, Cit, Arg, Val, Met, Lys, Ile, Leu, and Trp, were confirmed as significantly changed, and five types of amino acid-related metabolites, hKyn, AnthA, Kyn, QA, and NP, were confirmed as significantly changed. It was found that the blood concentration values ​​of the 10 types of amino acids and the five types of amino acid-related metabolites 6 weeks after the start of treatment that were significantly correlated with the treatment prognosis can be an index for predicting the treatment prognosis of immune checkpoint inhibitors.

[0120] Multivariate analysis was performed using the Cox proportional hazards model to determine the effect of plasma concentrations of amino acids and amino acid-related metabolites on overall survival, and a discriminant equation was created to predict the prognosis of immune checkpoint inhibitor treatment.

[0121] Regarding the variable selection in the multivariate analysis using the Cox proportional hazards model, when only amino acids were used as explanatory variables, the 21 types of amino acids were targeted regardless of the presence or absence of significant differences, and when a combination of amino acids and amino acid-related metabolites was used as explanatory variables, explanatory variables were selected based on P<0.15 in the univariate analysis. In addition, two-variable discriminants, three-variable discriminants, four-variable discriminants, five-variable discriminants, and six-variable discriminants were created. As shown below, the combinations of variables were shown for the top 100 discriminant performance two-variable discriminants, the top 100 discriminant performance three-variable discriminants, the top 100 discriminant performance four-variable discriminants, the top 100 discriminant performance five-variable discriminants, and the top 100 discriminant performance six-variable discriminants.

[0122] The combinations of variables in the two-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [101. Two-variable equation obtained from amino acids before the start of treatment]. The combinations of variables in the three-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [102. Three-variable equation obtained from amino acids before the start of treatment]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [103. Four-variable equation obtained from amino acids before the start of treatment]. The combinations of variables in the five-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [104. Five-variable equation obtained from amino acids before the start of treatment]. The combinations of variables in the six-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [105. Six-variable equation obtained from amino acids before the start of treatment].

[0123] The combinations of variables in the two-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [106. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the three-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [107. Three-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [108. Four-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the five-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [109. Five-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the top 100 discriminant equations of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [110. Equation of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment].

[0124] The combination of variables in the two-variable discriminant equations with the top 100 discriminant performances obtained from amino acids 6 weeks after the start of treatment is shown below in [111. Two-variable equation obtained from amino acids after the start of treatment]. The combination of variables in the three-variable discriminant equations with the top 100 discriminant performances obtained from amino acids 6 weeks after the start of treatment is shown below in [112. Three-variable equation obtained from amino acids after the start of treatment]. The combination of variables in the four-variable discriminant equations with the top 100 discriminant performances obtained from amino acids 6 weeks after the start of treatment is shown below in [113. Four-variable equation obtained from amino acids after the start of treatment]. The combination of variables in the five-variable discriminant equations with the top 100 discriminant performances obtained from amino acids 6 weeks after the start of treatment is shown below in [114. Five-variable equation obtained from amino acids after the start of treatment]. The combination of variables in the six-variable discriminant equations with the top 100 discriminant performances obtained from amino acids 6 weeks after the start of treatment is shown below in [115. Six-variable equation obtained from amino acids after the start of treatment].

[0125] The combinations of variables in the two-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites 6 weeks after the start of treatment are shown below in [116. Two-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment]. The combinations of variables in the three-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites 6 weeks after the start of treatment are shown below in [117. Three-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites 6 weeks after the start of treatment are shown below in [118. Four-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment]. The combinations of variables in the five-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites 6 weeks after the start of treatment are shown below in [119. Five-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment]. The combinations of variables in the top 100 six-variable discriminant equations with respect to discrimination performance obtained from amino acids and amino acid-related metabolites six weeks after the start of treatment are shown below in [120. Equation of five variables obtained from amino acids and amino acid-related metabolites after the start of treatment].

[0126] Figure 17 shows the distribution of C-indexes, which indicate the performance of the discriminants shown in [101. 2-variable equation obtained from amino acids before the start of treatment] to [120. 6-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment]. The horizontal axis represents the number of variables to be combined, and the vertical axis represents the C-index. In the figure, (A) shows the distribution of C-indexes corresponding to the discriminants obtained from the concentration values ​​of amino acids, and (B) shows the distribution of C-indexes corresponding to the discriminants obtained from the concentration values ​​of amino acids and amino acid-related metabolites. The distributions corresponding to the symbols A11, A21, A31, A41, A51, B11, B21, B31, B41, and B51 are the distributions of C-indexes corresponding to the discriminants obtained from the concentration values ​​before the start of treatment, and the distributions corresponding to the symbols A12, A22, A32, A42, A52, B12, B22, B32, B42, and B52 are the distributions of C-indexes corresponding to the discriminants obtained from the concentration values ​​6 weeks after the start of treatment.

[0127] Figure 18 shows the frequency of occurrence of variables in the discriminant equations shown in [101. Equation of two variables obtained from amino acids before the start of treatment] to [105. Equation of six variables obtained from amino acids before the start of treatment]. Figure 19 shows the frequency of occurrence of variables in the discriminant equations shown in [106. Equation of two variables obtained from amino acids and amino acid-related metabolites before the start of treatment] to [110. Equation of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment].

[0128] Figure 20 shows the frequency of occurrence of variables in the discriminant equations shown in [111. Equation of two variables obtained from amino acids after the start of treatment] to [115. Equation of six variables obtained from amino acids after the start of treatment]. Figure 21 shows the frequency of occurrence of variables in the discriminant equations shown in [116. Equation of two variables obtained from amino acids and amino acid-related metabolites after the start of treatment] to [120. Equation of six variables obtained from amino acids and amino acid-related metabolites after the start of treatment].

[0129] Figure 22 is a diagram explaining the discrimination performance of the discriminant created with the goal of minimizing AIC (Akaike Information Criterion) by the stepwise method among the above discriminants. The discriminant was created using four parameters consisting of Ser, Gly, Arg, and QA. The C-index, which indicates the performance of the created discriminant, was 0.775, and when the upper quartile was used as the cutoff value, the P value of the log-rank test was 3.97 × 10 -13 The risk ratio was 15.79. The discriminant equation created was able to predict the prognosis of immune checkpoint inhibitor treatment with high accuracy. EXAMPLES

[0130] The occurrence of side effects related to the treatment with immune checkpoint inhibitors was investigated for the lung cancer patients described in Example 1. Side effects related to the treatment with immune checkpoint inhibitors were observed in a total of 22 cases, including interstitial pneumonia (7 cases), pneumonia (10 cases), rash / pruritus (10 cases), enteritis / diarrhea (6 cases), fever (3 cases), hyperthyroidism (2 cases), fatigue (2 cases), arthralgia (1 case), taste disorder (1 case), and AST and ALT abnormalities (1 case). Of these, a total of 5 cases of interstitial pneumonia (2 cases), pneumonia (2 cases), and enteritis (1 case) were observed as Grade 3 or higher side effects according to the Common Terminology Criteria for Adverse Events (CTCAE).

[0131] A correlation analysis was performed between the concentration values ​​of the 21 amino acids and the 15 amino acid-related metabolites before the start of treatment and the risk of side effects associated with immune checkpoint inhibitor treatment. The analysis results are shown in FIG. 23. FIG. 23 shows the ROC_AUC and P value in the univariate correlation analysis between each amino acid and the risk of side effects. Seven types of amino acids, His, Ala, Arg, Pro, Tyr, Lys, and Trp, were confirmed as significantly changed amino acids, and one type of amino acid-related metabolite, hKyn, was confirmed as a significantly changed amino acid-related metabolite. It was found that the seven types of amino acids and the one type of amino acid-related metabolite that were significantly correlated with the risk of side effects can be indicators for predicting the risk of side effects caused by immune checkpoint inhibitors.

[0132] Multivariate analysis was performed using a logistic regression model to examine the effect of plasma concentrations of amino acids and amino acid-related metabolites on the risk of side effects, and a discriminant equation was created to determine the risk of side effects caused by immune checkpoint inhibitors.

[0133] Regarding the variable selection in the multivariate analysis by the logistic regression model, when only amino acids are used as explanatory variables, the 21 types were targeted regardless of the presence or absence of significant difference, and when a combination of amino acids and amino acid-related metabolites was used as explanatory variables, explanatory variables were selected based on P<0.20 in the univariate analysis. In addition, two-variable discriminants, three-variable discriminants, four-variable discriminants, five-variable discriminants, and six-variable discriminants were created. As shown below, the combinations of variables were shown for the two-variable discriminants in the top 100 discriminant performance, the three-variable discriminants in the top 100 discriminant performance, the four-variable discriminants in the top 100 discriminant performance, the five-variable discriminants in the top 100 discriminant performance, and the six-variable discriminants in the top 100 discriminant performance.

[0134] The combinations of variables in the two-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [201. Equation of two variables obtained from amino acids before the start of treatment]. The combinations of variables in the three-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [202. Equation of three variables obtained from amino acids before the start of treatment]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [203. Equation of four variables obtained from amino acids before the start of treatment]. The combinations of variables in the five-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [204. Equation of five variables obtained from amino acids before the start of treatment]. The combinations of variables in the six-variable discriminant equations with the top 100 discriminant performances obtained from amino acids before the start of treatment are shown below in [205. Equation of six variables obtained from amino acids before the start of treatment].

[0135] The combinations of variables in the two-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [206. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the three-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [207. Three-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [208. Four-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the five-variable discriminant equations with the top 100 discriminant performance obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [209. Five-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The combinations of variables in the top 100 discriminant equations of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment are shown below in [210. Equation of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment].

[0136] FIG. 24 shows the distribution of ROC_AUC, which represents the performance of the discriminant shown in [201. 2-variable equation obtained from amino acids before the start of treatment] to [210. 6-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment]. The horizontal axis is the number of variables to be combined, and the vertical axis is ROC_AUC. In the figure, the distributions corresponding to the symbols C11, C21, C31, C41, and C51 are the distributions of ROC_AUC corresponding to the discriminant obtained from the concentration values ​​of amino acids, and the distributions corresponding to the symbols C12, C22, C32, C42, and C52 are the distributions of ROC_AUC corresponding to the discriminant obtained from the concentration values ​​of amino acids and amino acid-related metabolites. It was shown that the discriminant created in this embodiment can create a discriminant with high accuracy for predicting side effects occurring after the start of treatment.

[0137] Figure 25 shows the frequency of occurrence of variables in the discriminant equations shown in [201. Equation of two variables obtained from amino acids before the start of treatment] to [205. Equation of six variables obtained from amino acids before the start of treatment]. Figure 26 shows the frequency of occurrence of variables in the discriminant equations shown in [206. Equation of two variables obtained from amino acids and amino acid-related metabolites before the start of treatment] to [210. Equation of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment]. EXAMPLES

[0138] For the lung cancer patients described in Example 1, the progression-free survival (PFS) and response rate, which are prognostic indicators of treatment with immune checkpoint inhibitors, were also analyzed. Blood samples were obtained from advanced and recurrent lung cancer patients scheduled for treatment with immune checkpoint inhibitors, and 19 types of amino acids (Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Trp, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, and Gly) and 8 types of amino acid-related metabolites (AnthA, hKyn, hTrp, Kyn, KynA, NP, QA, and XA) were analyzed. Nivolumab or pembrolizumab, which are anti-PD-1 antibodies, were used as antibody therapeutic agents.

[0139] Before the start of treatment, blood was collected from a peripheral vein, and the blood sample was promptly cooled after collection, and plasma was separated from the blood sample. The concentrations of free amino acids and amino acid-related metabolites in plasma were measured using an LC-MS analyzer or an LC-MS / MS analyzer according to the measurement method (A) described in the above embodiment. Background information on the patients, such as the progression and tissue type of cancer and clinical test values, was collected from the patients. In addition, the treatment response rate and treatment prognosis (progression-free survival (PFS)) for each patient were tracked for up to two years (average follow-up period 272 days) from the start of treatment.

[0140] A correlation analysis was performed between the concentration values ​​of the 19 types of amino acids and the 8 types of amino acid-related metabolites before the start of treatment and treatment prognosis (PFS: progression-free survival). In the analysis of PFS, events were observed in 46 of the 53 lung cancer patients analyzed. The analysis results are shown in Figure 27. Figure 27 shows the hazard ratio, P value, and C-Index in the univariate COX hazard analysis of each amino acid and each amino acid-related metabolite and PFS. Three types of amino acids, Ala, Arg, and Lys, were confirmed as significantly changed amino acids, and four types of amino acid-related metabolites, hKyn, AnthA, QA, and NP, were confirmed as significantly (P<0.05) changed amino acid-related metabolites (see the P value written in bold in Figure 27). It was found that the blood concentration values ​​of the three types of amino acids and the four types of amino acid-related metabolites before the start of treatment, which were significantly correlated with treatment prognosis, can be indicators for predicting the treatment prognosis of immune checkpoint inhibitors.

[0141] Multivariate analysis was performed using the Cox proportional hazards model to determine the effect of plasma amino acid and amino acid-related metabolite concentrations on PFS, and a linear discriminant equation was created to predict the prognosis of immune checkpoint inhibitor treatment. Death during the follow-up period was considered an event, and patients who were lost to follow-up due to treatment discontinuation due to side effects or transfer to another hospital were treated as censored patients.

[0142] Regarding variable selection in multivariate analysis using the Cox proportional hazards model, when only amino acids were used as explanatory variables, the 19 types of amino acids were selected regardless of whether there was a significant difference, and when a combination of amino acids and amino acid-related metabolites was used as explanatory variables, explanatory variables were selected based on P<0.20 in univariate analysis. In addition, discriminants with 2 variables, 3 variables, 4 variables, 5 variables, and 6 variables were created.

[0143] The combinations of variables and C-index values ​​in the two-variable discriminant equations ranked in the top 99 for discrimination performance are shown below in [301. Two-variable equation obtained from amino acids before the start of treatment using PFS as an evaluation index]. The combinations of variables and C-index values ​​in the three-variable discriminant equations ranked in the top 100 for discrimination performance are shown below in [302. Three-variable equation obtained from amino acids before the start of treatment using PFS as an evaluation index]. The combinations of variables and C-index values ​​in the four-variable discriminant equations ranked in the top 100 for discrimination performance are shown below in [303. Four-variable equation obtained from amino acids before the start of treatment using PFS as an evaluation index]. The combinations of variables and C-index values ​​in the five-variable discriminant equations ranked in the top 100 for discrimination performance are shown below in [304. Five-variable equation obtained from amino acids before the start of treatment using PFS as an evaluation index]. The combinations of variables and C-index values ​​in the six-variable discriminant equations ranked in the top 100 for discrimination performance are shown below in [305. Six-variable equation obtained from amino acids before the start of treatment using PFS as an evaluation index]. These combinations were determined from amino acids before the start of treatment, using PFS as an evaluation index.

[0144] The combinations of variables in the two-variable discriminant equations ranked in the top 100 for discrimination performance, and the C-index values ​​are shown below in [306. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index]. The combinations of variables in the three-variable discriminant equations ranked in the top 100 for discrimination performance, and the C-index values ​​are shown below in [307. Three-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index]. The combinations of variables in the four-variable discriminant equations ranked in the top 100 for discrimination performance, and the C-index values ​​are shown below in [ The combinations of variables in the top 100 discriminant equations for five variables and the C-index values ​​are shown below in [308.Equation of four variables obtained from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index], and the combinations of variables in the top 100 discriminant equations for six variables and the C-index values ​​are shown below in [310.Equation of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index]. Note that these combinations were obtained from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index.

[0145] In addition, we analyzed the response rate of immune checkpoint inhibitors. To evaluate the efficacy of immune checkpoint inhibitors, we performed a best response assessment according to the RECIST guidelines, Version 1.1 (EUROPEAN JOURNAL OF CANCER 45 (2009) 228-247). There were no complete responses (CR), but 16 cases had partial responses (PR), 9 cases had stable disease (SD), and 28 cases had progressive disease (PD). If PR was considered an effective response, the response rate was 30.2%.

[0146] A correlation analysis was performed between the concentration values ​​of the 19 amino acids and the 8 amino acid-related metabolites before the start of treatment and the therapeutic response rate. The analysis results are shown in FIG. 28. FIG. 28 shows the odds ratio, P value, and ROC_AUC in the univariate correlation analysis between each amino acid and each amino acid-related metabolite and the therapeutic response rate. No variables showing significant differences were observed, but two types of amino acids, Ala and Arg, were confirmed to show a significant tendency (P<0.1), and two types of amino acid-related metabolites, AnthA and NP, were confirmed to show a significant tendency (see the P values ​​written in bold in FIG. 28).

[0147] We performed multivariate analysis using a logistic regression model to examine the effect of plasma concentrations of amino acids and amino acid-related metabolites on therapeutic response rate, and created a discriminant equation to predict therapeutic response rate with immune checkpoint inhibitors.

[0148] Regarding variable selection in multivariate analysis using a logistic regression model, when only amino acids were used as explanatory variables, the 19 types of amino acids were selected regardless of whether there was a significant difference, and when a combination of amino acids and amino acid-related metabolites was used as explanatory variables, explanatory variables were selected based on P<0.30 in univariate analysis. In addition, discriminants with 2 variables, 3 variables, 4 variables, 5 variables, and 6 variables were created.

[0149] The combinations of variables in the two-variable discriminant equations with the top 87 discriminant performance and the ROC_AUC values ​​are shown below in [311. Two-variable equation obtained from amino acids before the start of treatment with response rate as an evaluation index]. The combinations of variables in the three-variable discriminant equations with the top 98 discriminant performance and the ROC_AUC values ​​are shown below in [312. Three-variable equation obtained from amino acids before the start of treatment with response rate as an evaluation index]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performance and the ROC_AUC values ​​are shown below in [313. Three-variable equation obtained from amino acids before the start of treatment with response rate as an evaluation index]. The combinations of variables in the top 100 discriminant equations with five variables and ROC_AUC values ​​are shown in the following [313. Formula of four variables obtained from amino acids before the start of treatment with response rate as an evaluation index], and the top 100 discriminant equations with six variables and ROC_AUC values ​​are shown in the following [314. Formula of five variables obtained from amino acids before the start of treatment with response rate as an evaluation index]. Note that these combinations were obtained from amino acids before the start of treatment with response rate as an evaluation index.

[0150] The combinations of variables in the two-variable discriminant equations with the top 99 discriminant performance and the ROC_AUC values ​​are shown below in [316. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment with response rate as an evaluation index]. The combinations of variables in the three-variable discriminant equations with the top 100 discriminant performance and the ROC_AUC values ​​are shown below in [317. Three-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment with response rate as an evaluation index]. The combinations of variables in the four-variable discriminant equations with the top 100 discriminant performance and the ROC_AUC values ​​are shown below in [3 The combinations of variables in the top 100 discriminant equations with five variables and ROC_AUC values ​​are shown below in [319. Equation of five variables obtained from amino acids and amino acid-related metabolites before the start of treatment with response rate as an evaluation index], and the combinations of variables in the top 100 discriminant equations with six variables and ROC_AUC values ​​are shown below in [320. Equation of six variables obtained from amino acids and amino acid-related metabolites before the start of treatment with response rate as an evaluation index]. Note that these combinations were obtained from amino acids and amino acid-related metabolites before the start of treatment with response rate as an evaluation index. [Industrial Applicability]

[0151] As described above, the present invention can be widely implemented in many industrial fields, particularly in the fields of pharmaceuticals, food, and medicine, and is particularly useful in the field of bioinformatics for predicting the prognosis of immune checkpoint inhibitor treatment and determining the occurrence of side effects. [Explanation of symbols]

[0152] 100 Evaluation Device 102 Control section 102a Receiving section 102b Specified part 102c Expression Creation Section 102d Evaluation Section 102d1 Calculation part 102d2 Converter 102d3 Generation part 102d4 Classification section 102e Result output section 102f Transmitter 104 Communication interface section 106 Storage section 106a Concentration data file 106b Index status information file 106c Specified index status information file 106d type related information database 106d1 Formula File 106e Evaluation result file 108 Input / Output Interface Section 112 Input Devices 114 Output Device 200 Client device (terminal device (information communication terminal device)) 300 Network 400 Database device

[0153] [101. Two-variable equation obtained from amino acids before the start of treatment] Arg,Met, 0.76; Arg,Phe, 0.753; Arg,Ile, 0.741; Arg,Lys, 0.737; Arg,Tyr, 0.73; Arg,Leu, 0.729; His,Phe, 0.729; Gly,Arg, 0.729; Arg,ABA, 0.727; Glu,Arg, 0.725; His,Met, 0.725; Arg,Val, 0.724; Thr,Arg, 0.72; Arg,Pro, 0.718; Gln,Arg, 0.711; His,ABA, 0.711; Asn,Arg, 0.706; His,Leu, 0.706; Arg,Trp, 0.703; Ser,Arg, 0.702; Phe,Trp, 0.701; Gly,His, 0.701; His,Arg, 0.699; His,Val, 0.698; Ala,Arg, 0.697; Cit,Arg, 0.697; Arg,Orn, 0.696; His,Tyr, 0.696; Gly,Cit, 0.695; His,Pro, 0.694; Asn,His, 0.693; Gly,Trp, 0.691; His,Orn, 0.691; Ser,His, 0.69; Ala,Phe, 0.689; Glu,His, 0.689; Gln,His, 0.688; Gly,Ala, 0.687; His,Cit, 0.687; Asn,Cit, 0.687; Ala,Cit, 0.686; Met,Trp, 0.683; His,Lys, 0.683; Glu,Cit, 0.68; His,Thr, 0.679; Tyr,Trp, 0.679; Ser,Cit, 0.678; Cit,Phe, 0.676; His,Ala, 0.674; His,Trp, 0.673; Ala,Met, 0.668; Ala,Orn, 0.667; Ala,Leu, 0.666; Ala,Ile, 0.665; Leu,Trp, 0.664; ABA,Trp, 0.662; Ser,Ala, 0.661; Thr,Cit, 0.661; Ala,Tyr, 0.661; Cit,Tyr, 0.661; Val,Phe, 0.66; Glu,Trp, 0.66; Glu,Ala, 0.658; Gly,Orn, 0.658; Ile,Trp, 0.657; Ser,Trp, 0.657; Ala,Pro, 0.655; Ala,Val, 0.654; Gly,Lys, 0.654; Ala,ABA, 0.654; Cit,Val, 0.654; Ala,Trp, 0.653; Gln,Ala, 0.65; Thr,Phe, 0.649; Gly,Thr, 0.649; Orn,Trp, 0.648; Thr,Ala, 0.647; Ala,Lys, 0.646; Gly,Val, 0.645; Cit,Lys, 0.645; Asn,Ala, 0.645; Lys,Phe, 0.643; Pro,Trp, 0.642; Lys,Trp, 0.641; Gln,Trp, 0.638; Thr,ABA, 0.638; Tyr,Phe, 0.637; Asn,Trp, 0.636; Thr,Ile, 0.636; Thr,Tyr, 0.633; Glu,Thr, Thr,Orn, 0.63; Ser,Thr, 0.629; Thr,Val, 0.629; Thr,Pro, 0.629; Thr,Lys, 0.627; Asn,Thr, 0.626; Gln,Thr, 0.625; Thr,Met, 0.622; Thr,Leu, 0.621.

[0154] [102. Three-variable equation obtained from amino acids before the start of treatment] Ala,Arg,Met, 0.784; His,Arg,Met, 0.781; Arg,Met,Trp, 0.777; Ala,Arg,Phe, 0.776; Arg,Met,Phe, 0.771; Glu,Arg,Met, 0.771; Arg,Val,Phe, 0.769; Arg,Val,Met, 0.768; Arg,ABA,Met, 0.764; Arg,Tyr,Met, 0.763; Gln,Arg,Met, 0.763; Arg,Met,Leu, 0.763; Thr,Arg,Met, 0.762; Arg,Met,Lys, 0.762; Ser,Arg,Phe, 0.762; Arg,Met,Orn, 0.76; Ala,Arg,Lys, 0.76; Arg,Phe,Trp, 0.759; Arg,Met,Ile, 0.759; Cit,Arg,Met, 0.759; Arg,Pro,Met, 0.756; Asn,Arg,Phe, 0.755; Arg,Orn,Phe, 0.755; Arg,Ile,Phe, 0.754; Arg,Pro,Phe, 0.754; Arg,Leu,Phe, 0.754; Gly,Arg,Phe, 0.754; Arg,Tyr,Phe, 0.753; Arg,Lys,Phe, 0.752; His,Arg,Phe, 0.752; Cit,Arg,Phe, 0.75; Glu,Arg,Ile, 0.748; Gly,Thr,Arg, 0.748; Arg,Pro,Ile, 0.746; Arg,Tyr,Lys, 0.745; Arg,Pro,Lys, 0.745; Arg,Val,Ile, 0.743; Arg,Tyr,Ile, 0.742; Gly,Arg,Ile, 0.742; Thr,Arg,Ile, 0.742; Cit,Arg,Ile, 0.742; Arg,Lys,Leu, 0.741; Arg,Orn,Lion, 0.741; His,Arg,Ile, 0.74; Asn,Arg,Ile, 0.74; Arg,ABA,Tyr, 0.74; Gly,Arg,Lys, 0.74; Arg,Ile,Trp, 0.739; Ala,Arg,Ile, 0.739; Gln,Arg,Ile,0.739; Gly,Gln,Arg, 0.739; Arg,Leu,Trp, 0.738; Ala,Arg,Tyr, 0.738; His,Arg,Lys, 0.738; Gly,Arg,ABA, 0.738; Arg,Pro,ABA, 0.737; Ser,Arg,Leu, 0.737; Gly,Arg,Leu, 0.737; Glu,Arg,ABA, 0.737; Arg,ABA,Ile, 0.736; Arg,Pro,Leu, 0.736; Glu,Arg,Leu, 0.736; Gln,Arg,ABA, 0.736; Gln,Arg,Leu, 0.735; Ala,Arg,Leu, 0.735; Arg,Pro,Val, 0.735; His, Arg, Leu, 0.734; Arg, Val, Lys, 0.734; Glu,Arg,Tyr, 0.734; Arg,Pro,Tyr, 0.734; Gln,Arg,Lys, 0.734; Arg, Tyr, Leu, 0.733; Arg,Val,Leu, 0.733; Asn,Arg,Tyr, 0.733; Thr,Arg,ABA, 0.732; Gln,Arg,Val, 0.731; Glu,Ala,Arg, 0.731; Ala,Orn,Phe, 0.73; Thr,Arg,Leu, 0.73; Arg,Tyr,Val, 0.73; Ser,Arg,Tyr, 0.73; Glu,Gly,Arg, 0.73; Arg,Val,Trp, 0.729; Gln,Arg,Tyr, 0.729; Arg,ABA,Leu, 0.729; Ser,Gly,Arg, 0.729; Thr,Arg,Tyr, 0.729; Arg,ABA,Trp, 0.728; Arg,ABA,Lys, 0.728; Gly,Arg,Trp, 0.728; Cit,Arg,Tyr, 0.728; Ser,Arg,ABA, 0.728; Glu,Asn,Arg, 0.727; His,Arg,ABA, 0.727; Ala,Arg,Val, 0.726; Ala,Arg,ABA, 0.726; Glu,Arg,Trp, 0.725; Gly,Ala,Arg, 0.723; Asn,Arg,ABA, 0.722; Ala,Arg,Pro, 0.721.

[0155] [103. Four-variable equation obtained from amino acids before the start of treatment] Glu,Arg,Met,Trp, 0.798; Gly,Arg,Met,Trp, 0.796; Gly,Ala,Arg,Met, 0.793; Ala,Arg,Met,Lys, 0.793; Glu,Ala,Arg,Met, 0.792; Ala,Arg,Met,Trp, 0.79; Ala,Arg,Met,Leu, 0.789; His,Arg,Tyr,Met, 0.789; Gly,His,Arg,Met, 0.788; His,Arg,Met,Orn, 0.788; Arg,Met,Phe,Trp, 0.787; Ala,Arg,Met,Phe, 0.787; Thr,Ala,Arg,Met, 0.787; Arg,Met,Ile,Trp, 0.786; Gln,His,Arg,Met, 0.786; Ala,Arg,Val,Met, 0.785; Ala,Arg,Tyr,Met, 0.785; Ala,Cit,Arg,Met, 0.784; Ala,Arg,Tyr,Phe, 0.784; Ala,Arg,ABA,Met, 0.783; Gln,Ala,Arg,Met, 0.783; Ala,Arg,Pro,Met, 0.783; Arg,Val,Met,Trp, 0.782; Arg,Met,Lys,Trp, 0.782; His,Arg,Pro,Met, 0.782; Arg,Met,Leu,Phe, 0.781; His,Arg,Met,Leu, 0.781; Gly,Arg,Val,Met, 0.781; Gly,Arg,Met,Leu, 0.779; Gln,Arg,Met,Phe, 0.779; Asn,Arg,Met,Leu, 0.779; Glu,Arg,Val,Met, 0.778; Arg,Tyr,Met,Trp, 0.777; Gln,His,Arg,Phe, 0.777; Thr,Arg,Met,Trp, 0.776; Glu,Arg,Tyr,Met, 0.776; Gly,Arg,Met,Lys, 0.776; Glu,Arg,Met,Phe, 0.775; Ala,Arg,ABA,Phe, 0.775; Arg,ABA,Met,Phe, 0.774; Asn,Arg,Met,Ile, 0.773; Gly,Ala,Arg,Phe, 0.773; Asn,Gln,Arg,Met, 0.772; Glu,Asn,Arg,Met, 0.772; Gly,Arg,Tyr,Met, 0.772; Gln,Thr,Arg,Phe, 0.772; Asn,Arg,Val,Met, 0.771; Arg,Met,Ile,Phe, 0.771; Gln,Arg,Val,Phe, 0.771; Gly,Arg,ABA,Met, 0.771; Gly,Thr,Arg,Met, 0.77; Asn,Arg,Met,Orn, 0.77; Glu,Ala,Arg,Phe, 0.77; Arg,Val,Met,Orn, 0.769; Ser,Arg,Pro,Phe, 0.769; Gly,Arg,Val,Phe, 0.769; Asn,Arg,Pro,Met, 0.768; Ala,Arg,Orn,Phe, 0.768; Glu,Gln,Arg,Met, 0.768; Glu,Arg,Met,Orn, 0.768; Thr,Arg,Val,Phe, 0.768; Ser,Arg,Phe,Trp, 0.767; Arg,Pro,Met,Phe, 0.767; Arg,Val,Leu,Phe, 0.767; Gly,Arg,Pro,Met, 0.767; Glu,Cit,Arg,Met, 0.767; Arg,Val,Met,Ile, 0.767; Ala,Cit,Arg,Phe, 0.767; Gln,Arg,Val,Met, 0.767; Gln,Arg,Met,Lys, 0.766; Ser,Arg,Tyr,Met, 0.765; Arg,Val,Orn,Phe, 0.765; Arg,Pro,ABA,Met, 0.764; Gln,Arg,Met,Ile, 0.764; Asn,Gln,Arg,Phe, 0.764; Glu,Thr,Arg,Met, 0.763; Arg,Tyr,Met,Ile, 0.763; Ser,Arg,Met,Lys, 0.763; Thr,Arg,ABA,Met, 0.763; Thr,Arg,Met,Leu, 0.763; Arg,Pro,Tyr,Met, 0.763; Arg,ABA,Met,Orn, 0.763; Ser,Arg,Met,Leu, 0.763; Gln,Arg,Met,Orn, 0.763; Gln,Cit,Arg,Met, 0.763; Cit,Arg,Val,Phe, 0.763; Ser,Thr,Arg,Met, 0.762; Arg,Val,Phe,Trp, 0.762; Thr,Arg,Phe,Trp, 0.761; Arg,Met,Orn,Lys, 0.761; Thr,Arg,Pro,Met, 0.76; Arg,Pro,Phe,Trp, 0.759; Arg,ABA,Phe,Trp, 0.755; Gln,Arg,Pro,Met, 0.755; Arg,Tyr,Phe,Trp, 0.754; Arg,Orn,Lys,Phe, 0.753; Arg,Orn,Phe,Trp, 0.752; Arg,Lys,Phe,Trp, 0.751; Arg,Lys,Ile,Phe, 0.747; Arg,Tyr,Ile,Trp, 0.741.

[0156] [104. Five-variable equation obtained from amino acids before the start of treatment] Ala,Arg,Met,Leu,Phe, 0.805; Ala,Arg,Met,Lys,Trp, 0.805; Ala,Arg,Val,Met,Phe, 0.803; Gly,Ala,Arg,Met,Ile, 0.8; Gln,Ala,Arg,Met,Phe, 0.796; Ala,Arg,Met,Phe,Trp, 0.796; Asn,Ala,Arg,Met,Trp, 0.796; Arg,Met,Lys,Phe,Trp, 0.796; Ser,Gly,Arg,Met,Trp, 0.796; Gly,Ala,Arg,Met,Trp, 0.795; Ala,Arg,Pro,Met,Trp, 0.795; Gln,His,Arg,Met,Trp, 0.795; Ser,Ala,Arg,Met,Trp, 0.794; Arg,Val,Met,Phe,Trp, 0.794; Glu,Gly,Ala,Arg,Met, 0.794; His,Cit,Arg,Met,Orn, 0.794; Ala,Arg,Met,Leu,Trp, 0.793; Arg,ABA,Met,Phe,Trp, 0.793; His,Cit,Arg,Met,Phe, 0.793; Ala,Arg,Met,Lys,Phe, 0.792; Ala,Cit,Arg,Met,Trp, 0.792; Gln,Ala,Arg,Met,Trp, 0.792; Arg,Met,Leu,Phe,Trp, 0.792; Cit,Arg,Met,Phe,Trp, 0.792; Gly,His,Arg,Met,Trp, 0.792; His,Ala,Arg,Met,Phe, 0.792; Ala,Arg,Val,Met,Lys, 0.792; His,Ala,Arg,Met,Trp, 0.791; Gln,Arg,Met,Phe,Trp, 0.791; Ala,Arg,Tyr,Val,Met, 0.791; Gln,Ala,Arg,Met,Leu, 0.79; Ala,Cit,Arg,Met,Ile, 0.79; Asn,Ala,Arg,Met,Phe, 0.789; Ala,Arg,Tyr,Met,Lys, 0.789; Asn,His,Arg,Tyr,Met, 0.789; Glu,Gly,Arg,Val,Met, 0.789; Ser,Arg,Met,Phe,Trp, 0.788; Ala,Arg,Met,Ile,Leu, 0.788; Thr,Ala,Arg,ABA,Met, 0.788; Ser,Ala,Arg,Met,Leu, 0.788; Glu,His,Arg,Met,Ile, 0.788; Thr,Ala,Arg,Met,Phe, 0.787; Ser,Ala,Arg,Met,Phe, 0.787; Glu,His,Arg,Met,Phe, 0.787; His,Arg,ABA,Met,Leu, 0.787; Ser,Ala,Arg,Met,Ile, 0.786; Arg,ABA,Val,Met,Trp, 0.786; Ala,Arg,ABA,Met,Phe, 0.785; Ser,His,Ala,Arg,Met, 0.785; His,Ala,Cit,Arg,Met, 0.785; Gly,Gln,Arg,Val,Met, 0.785; Glu,Ser,His,Arg,Met, 0.784; Asn,Arg,Pro,Met,Trp, 0.783; Arg,Met,Orn,Lys,Trp, 0.783; Glu,His,Arg,Met,Lys, 0.783; Arg,Val,Ile,Phe,Trp, 0.782; Asn,Arg,Val,Met,Trp, 0.782; Gln,Arg,Met,Leu,Trp, 0.782; His,Ala,Arg,Pro,Met, 0.782; Ser,Gln,Ala,Arg,Phe, 0.782; His,Arg,Met,Orn,Leu, 0.782; Arg,Tyr,Met,Leu,Trp, 0.78; Gln,Arg,Met,Orn,Phe, 0.779; Gln,Arg,Met,Ile,Phe, 0.779; Cit,Arg,Val,Ile,Phe, 0.778; His,Thr,Arg,Val,Met, 0.778; Glu,Arg,Tyr,Met,Phe, 0.778; Asn,His,Arg,Pro,Met, 0.778; Gly,Arg,Tyr,Val,Met, 0.778; Glu,Arg,Met,Orne,Phe, 0.778; Ala,Arg,Pro,Val,Phe, 0.777; Asn,Arg,Tyr,Val,Met, 0.777; Asn,Gly,Arg,ABA,Met, 0.776; Ser,Arg,Ile,Phe,Trp, 0.775; Ala,Arg,Orn,Ile,Phe, 0.775; Arg,Pro,Ile,Leu,Phe, 0.774; Gln,Ala,Arg,Val,Phe, 0.773; Asn,Thr,Arg,Met,Orn, 0.773; Ser,Thr,Arg,Met,Phe, 0.773; Thr,Ala,Arg,Phe,Trp, 0.772; Ala,Arg,Pro,Phe,Trp, 0.772; Gly,His,Thr,Arg,Met, 0.771; Asn,Thr,Arg,Met,Ile, 0.771; Thr,Arg,ABA,Met,Leu, 0.77; Ala,Arg,Orn,Lys,Phe, 0.769; Thr,Arg,Lys,Phe,Trp, 0.769; Asn,Ala,Arg,Val,Phe, 0.769; Glu,Asn,Thr,Arg,Met, 0.769; Arg,Tyr,Ile,Leu,Phe, 0.768; Thr,Cit,Arg,Met,Phe, 0.768; Glu,Thr,Arg,ABA,Met, 0.767; Ala,Arg,Lys,Phe,Trp, 0.766; Asn,Ala,Arg,Lys,Phe, 0.765; Thr,Arg,ABA,Met,Orn, 0.765; Arg,Val,Lys,Phe,Trp, 0.761; Thr,Arg,Tyr,Phe,Trp, 0.761; Thr,Arg,Val,Met,Lys, 0.76; Thr,Ala,Arg,Lys,Phe, 0.758; Arg,Orn,Lys,Phe,Trp, 0.753; His,Arg,Lys,Phe,Trp, 0.752.

[0157] [105.You can see the story behind the scenes] Glu,Ala,Arg,Met,Leu,Phe, 0.821; His, Arg, Val, Met, Lys, Phe, 0.82; Gly,Ala,Arg,Val,Met,Phe, 0.817; Glu,Ala,Arg,Val,Met,Phe, 0.813; Glu,Asn,Ala,Arg,Met,Trp, 0.811; Gly,Ala,Arg,Val,Met,Lys, 0.81; Ala,Arg,Val,Met,Lys,Phe, 0.809; Ala,Arg,Val,Met,Orn,Phe, 0.809; Gly,His,Ala,Arg,Met,Leu, 0.809; Ala,Arg,Val,Met,Phe,Trp, 0.808; Glu,Ala,Cit,Arg,Met,Trp, 0.806; Glu,Ala,Arg,Tyr,Met,Trp, 0.806; Glu,Ala,Arg,Met,Phe,Trp, 0.804; Gly,Ala,Arg,Met,Phe,Trp, 0.803; Ser,Ala,Arg,Val,Met,Phe, 0.803; Gly,Ala,Cit,Arg,Val,Met,0.803; Thr,Ala,Arg,Met,Phe,Trp, 0.802; Glu,Ala,Arg,Pro,Met,Phe, 0.802; Ala,Arg,Met,Ile,Phe,Trp, 0.801; Glu,Ser,Ala,Arg,Met,Trp, 0.801; Gly,Gln,Ala,Arg,Met,Lys, 0.801; Gly,Ala,Arg,Met,Leu,Trp, 0.8; Glu,Arg,Met,Orn,Phe,Trp, 0.8; Ala,Arg,Pro,Ile,Leu,Phe, 0.8; Gln,Ala,Arg,Met,Phe,Trp, 0.799; Ser,Ala,Arg,Met,Phe,Trp, 0.799; Glu,Asn,Arg,Met,Phe,Trp, 0.799; Glu,Arg,Tyr,Met,Orn,Trp, 0.799; Glu,Gln,Arg,Met,Lys,Trp, 0.799; Gly,Ala,Arg,Pro,Met,Trp, 0.798; Glu,Ser,Ala,Arg,Met,Phe, 0.798; Glu,Gln,His,Arg,Met,Trp, 0.798; His,Ala,Arg,Met,Phe,Trp, 0.797; Gly,Gln,Ala,Arg,Met,Trp, 0.797; Glu,Arg,Met,Ile,Phe,Trp, 0.797; Glu,Ala,Arg,ABA,Met,Orn, 0.797; Arg,ABA,Met,Leu,Phe,Trp, 0.796; Glu,Arg,ABA,Met,Orn,Trp, 0.796; Ala,Arg,ABA,Met,Lys,Phe, 0.796; Gly,Gln,Thr,Ala,Arg,Met, 0.796; Ala,Arg,Val,Met,Lys,Leu, 0.796; Ser,Ala,Arg,Met,Lys,Trp, 0.795; Ala,Cit,Arg,Val,Met,Trp, 0.795; Gly,Gln,Arg,Met,Phe,Trp, 0.795; Ser,Ala,Arg,Val,Met,Trp, 0.795; Arg,Pro,Met,Lys,Phe,Trp, 0.795; Glu,Asn,Gly,Arg,Met,Trp, 0.795; Glu,Asn,Ala,Arg,Met,Ile, 0.795; Ser,Ala,Arg,Val,Met,Lys, 0.795; Gln,Ala,Arg,Met,Lys,Leu, 0.795; Ala,Arg,Val,Met,Lys,Ile, 0.795; Ala,Arg,Tyr,Met,Phe,Trp, 0.794; Gly,Ala,Cit,Arg,Met,Trp, 0.794; Gly,Thr,Ala,Arg,Met,Ile, 0.794; Ala,Arg,Pro,Val,Met,Trp, 0.794; Gly,Thr,Ala,Arg,Tyr,Met, 0.794; His, Arg, Tyr, Met, Lys, Trp, 0.794; Glu,Ser,Arg,Met,Ile,Trp, 0.794; Glu,Ala,Arg,Met,Lys,Phe, 0.793; Ala,Cit,Arg,Pro,Met,Trp, 0.793; Glu,His,Ala,Arg,Met,Phe, 0.793; Gln,Ala,Arg,Val,Ile,Phe, 0.793; Glu,Asn,Ala,Arg,ABA,Met, 0.793; Thr,Cit,Arg,Met,Phe,Trp, 0.792; Ala,Cit,Arg,Val,Met,Lys, 0.792; Asn,Ala,Arg,Met,Ile,Phe, 0.791; Gln,Ala,Arg,Met,Ile,Trp, 0.791; Ala,Arg,Tyr,Val,Met,Lys, 0.791; His,Ala,Arg,Val,Met,Trp, 0.79; Gln,Arg,Met,Orn,Phe,Trp, 0.79; Arg,Pro,ABA,Met,Phe,Trp, 0.79; His,Thr,Ala,Arg,Tyr,Met, 0.789; Gln,Thr,Ala,Arg,Met,Trp, 0.788; Asn,Gln,Arg,ABA,Met,Trp, 0.788; Ser,His,Arg,Met,Ile,Trp, 0.788; Glu,Ser,Ala,Cit,Arg,Met, 0.788; Thr,Arg,Met,Ile,Phe,Trp, 0.788; Gln,His,Thr,Ala,Arg,Met, 0.788; Thr,Ala,Arg,Pro,Tyr,Met, 0.788; Asn,Gln,Ala,Arg,Met,Leu, 0.788; Thr,Ala,Arg,Tyr,Met,Ile, 0.787; Ser,Ala,Arg,Val,Lys,Phe, 0.787; Gln,Thr,Ala,Arg,Met,Ile, 0.786; Thr,Ala,Arg,Tyr,Met,Lys, 0.786; Asn, Arg, ABA, Tyr, Met, Trp, 0.786; Ser,Ala,Arg,Val,Met,Ile, 0.786; Ala,Arg,ABA,Val,Lys,Phe, 0.785; His,Arg,Tyr,Val,Met,Trp, 0.785; Thr,Ala,Arg,Val,Lys,Phe, 0.784; Ala,Arg,Val,Lys,Leu,Phe, 0.784; Asn,Gln,Ala,Arg,Met,Orn, 0.784; Asn,Thr,Arg,Pro,Met,Trp, 0.783; Ser,Asn,Arg,Val,Met,Trp, 0.782; Asn,Gly,Arg,Pro,Met,Trp, 0.781; Ala,Arg,Val,Lys,Phe,Trp, 0.78; Gly,Ala,Arg,Val,Lys,Phe, 0.78; Ser,Asn,Thr,Arg,Met,Trp, 0.778; 0.778; Thr,Arg,Pro,Met,Ile,Trp, 0.774; Ser,Arg,Pro,Met,Lys,Trp, 0.773.

[0158] [106. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment] Arg,Kyn, 0.771; Arg,hKyn, 0.741; Cit,QA, 0.738; Arg,Lys, 0.737; His,QA, 0.736; Arg,QA, 0.735; hKyn,AnthA, 0.731; His,hKyn, 0.729; Gly,Arg, 0.729; Arg,hAnthA, 0.728; His,AnthA, 0.726; Cit,hKyn, 0.722; His,Kyn, 0.722; Arg,NP, 0.721; Thr,Arg, 0.72; AnthA,Kyn, 0.72; Trp,hKyn, 0.719; AnthA,QA, 0.716; Arg,AnthA, 0.715; Cit, Kyn, 0.713; hTrp,AnthA, 0.712; His,hTrp, 0.712; His,hAnthA, 0.711; Cit,NP, 0.71; Ala,hKyn, 0.709; Ala, Kyn, 0.708; Ala,AnthA, 0.707; Asn,Arg, 0.706; Arg,hTrp, 0.704; Arg,Trp, 0.703; Ser,Arg, 0.702; Gly,His, 0.701; Lys,hKyn, 0.7; His,Arg, 0.699; AnthA,NP, 0.699; Ala,Arg, 0.697; Cit,Arg, 0.697; Thr,hKyn, 0.697; His,NP, 0.697; Arg,Orn, 0.696; Ala,QA, 0.695; Gly,Cit, 0.695; Trp,Kyn, 0.694; Gly,Trp, 0.691; His,Orn, 0.691; Trp,hAnthA, 0.689; Gly,hKyn, 0.689; hKyn,hTrp, 0.689; Orn,hKyn, 0.689; hKyn,NP, 0.688; Gly,Ala, 0.687; His,Cit, 0.687; Ala,Cit, 0.686; Cit,hTrp, 0.686; Cit,hAnthA, 0.685; Cit,AnthA, 0.684; Trp,AnthA, 0.683; Asn,hKyn, 0.681; Cit,Trp, 0.68; Lys,AnthA, 0.68; Ser,hKyn, 0.679; His,Thr, 0.679; Gly,AnthA, 0.679; Ala,hAnthA, 0.678; Ser,Cit, 0.678; hTrp,QA, 0.677; 0.673; Trp,QA, 0.673; Gly,QA, 0.671; hAnthA,AnthA, 0.671; Asn,AnthA, 0.671; Orn,NP, 0.67; Ala,NP, 0.669; 0.668; Ala, Orn, 0.667; hKyn,hAnthA, 0.667; Ala,hTrp, 0.664; hKyn,Kyn, 0.664; Ser,Ala, 0.661; Thr,Cit, 0.661; Thr,hAnthA, 0.654; Lys,hAnthA, 0.654; Ala,Trp, 0.653; Trp,hTrp, 0.651; Thr,NP, 0.649; Orn,Trp, 0.648; Thr,Ala, 0.647; Cit,Lys, 0.645; Lys,Trp, 0.641; Asn,Trp, 0.636; Thr,hTrp, 0.631; hAnthA,NP, 0.62.

[0159] [107. Three-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment] Thr,Arg,Kyn, 0.771; Arg,Kyn,NP, 0.771; Arg, Lys, Kyn, 0.77; Arg,AnthA,Kyn, 0.769; His,Arg,Kyn, 0.769; Asn,Arg,Kyn, 0.769; Arg,hTrp,Kyn, 0.768; Gly, Arg, Kyn, 0.767; Arg,Orn,Kyn, 0.767; Ala,Arg,Kyn, 0.766; Arg,Kyn,QA, 0.766; Ser,Arg,Kyn, 0.763; Thr,Arg,QA, 0.763; Arg,hKyn,Kyn, 0.761; Ala,hKyn,AnthA, 0.76; Arg,hAnthA,Kyn, 0.757; Arg,Lys,QA, 0.757; Trp,hKyn,AnthA, 0.755; Arg,hKyn,AnthA, 0.754; Arg,hAnthA,QA, 0.753; Arg,hTrp,QA, 0.75; Gly,Thr,Arg, 0.748; Arg,Lys,hKyn, 0.747; Asn,Arg,QA, 0.746; Thr,Arg,hKyn, 0.746; Cit,AnthA,QA, 0.746; Arg,hKyn,QA, 0.745; Arg,Trp,QA, 0.745; Gly,Arg,hKyn, 0.744; Ala,Cit,Kyn, 0.744; Arg,AnthA,QA, 0.743; Arg,hKyn,hAnthA, 0.742; Arg,Lys,NP, 0.742; Arg,hKyn,hTrp, 0.741; Arg,Orn,hKyn, 0.741; Arg,hKyn,NP, 0.741; His,Arg,hKyn, 0.741; Ala,Arg,hAnthA, 0.74; Cit,hKyn,AnthA, 0.74; Arg,Lys,hTrp, 0.74; Cit,hAnthA,QA, 0.74; Arg,Lys,AnthA, 0.739; Cit,Arg,hKyn, 0.739; Cit,Arg,QA, 0.739; Arg,Lys,Trp, 0.739; His,Arg,Lys, 0.738; Arg,hAnthA,AnthA, 0.738; Thr,Arg,hAnthA, 0.738; Ser,Arg,QA, 0.737; Ala,Arg,QA, 0.737; Arg,Orn,QA, 0.737; Thr,Arg,Lys, 0.737; His,Arg,QA, 0.736; Arg,Orn,Lys, 0.736; Arg,hAnthA,NP, 0.735; Arg,QA,NP, 0.735; Thr,Arg,NP, 0.735; Ser,Arg,Lys, 0.735; Ser,Arg,hAnthA, 0.734; Asn,Gly,Arg, 0.734; Asn,Arg,Lys, 0.734; Cit,hKyn,QA, 0.733; Arg,hAnthA,hTrp, 0.732; Gly,Arg,AnthA, 0.732; Arg,AnthA,NP, 0.731; Gly,Arg,NP, 0.731; Gly,Arg,hAnthA, 0.73; Gly,Arg,hTrp, 0.73; Arg,Orn,hAnthA, 0.729; Thr,Arg,Trp, 0.729; Asn,Arg,hAnthA, 0.729; Ser,Gly,Arg, 0.729; Asn,Arg,AnthA, 0.728; Gly,Arg,Trp, 0.728; Thr,Arg,hTrp, 0.728; Gly,His,Arg, 0.728; Arg,hTrp,AnthA, 0.727; Thr,hKyn,AnthA, 0.727; Gly,Arg,Orn, 0.727; Ala,hAnthA,AnthA, 0.725; Cit,Arg,hAnthA, 0.724; Arg,hTrp,NP, 0.724; Gly,Ala,Arg, 0.723; Ala,Arg,AnthA, 0.721; Ser,Arg,NP, 0.721; Asn,Arg,NP, 0.72; Arg,Orn,AnthA, 0.717; Cit,Arg,AnthA, 0.717; Arg,Trp,NP, 0.717; Ser,Arg,AnthA, 0.715; His,Arg,AnthA, 0.715; Asn,Arg,hTrp, 0.714; Cit,Trp,hKyn, 0.714; His,Arg,hTrp, 0.711; Asn,Ala,Arg, 0.709; Ala,Arg,hTrp, 0.709; Arg,Trp,hTrp, 0.706; Asn,Arg,Trp, 0.704; Arg,Orn,hTrp, 0.702; Cit,Trp,hAnthA, 0.696.

[0160] [108. Four-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment] Ser,Gly,Arg,QA, 0.775; Thr,Arg,hTrp,Kyn, 0.773; His,Arg,AnthA,Kyn, 0.771; Ala,Arg,Lys,Kyn, 0.769; Ala,Arg,Lys,QA, 0.769; Ser,Arg,hTrp,Kyn, 0.768; Arg,Orn,hTrp,Kyn, 0.768; Thr,Arg,Lys,Kyn, 0.767; Ala,Arg,Orn,Kyn, 0.767; Asn,Gly,Arg,Kyn, 0.767; Ala, Arg, hAnthA, Kyn, 0.766; Arg,AnthA,Kyn,QA, 0.766; Asn,Arg,Trp,Kyn, 0.766; Thr,Arg,Kyn,QA, 0.766; Arg,hKyn,Kyn,NP, 0.766; Ala,Arg,Trp,Kyn, 0.766; Thr,Arg,Lys,QA, 0.765; Ser,Arg,HAnthA,QA, 0.764; Arg,Lys,AnthA,Kyn, 0.764; Thr,Arg,HA,Kyn, 0.764; His,Arg,hTrp,Kyn, 0.764; Ser,Ala,Arg,Kyn, 0.764; Ser,Arg,AnthA,Kyn, 0.764; Arg,hKyn,hTrp,Kyn, 0.763; Arg,Iron,Lys,Kyn, 0.763; His,Arg,hKyn,Kyn, 0.763; Arg,hAnthA,hTrp,Kyn, 0.763; Arg,Lys,hKyn,Kyn, 0.763; Thr,Arg,hKyn,AnthA, 0.763; Ser,Arg,anthA,Kyn, 0.762; Arg,Lys,hAnthA,Kyn, 0.762; Gly,Arg,hKyn,AnthA, 0.761; Asn,Arg,hKyn,Kyn, 0.761; Gly,Cit,Arg,QA, 0.76; His,Arg,Lys,NP, 0.76; Arg,Lys,hKyn,AnthA, 0.759; Arg,Lys,AnthA,QA, 0.759; Cit,Arg,Lys,QA, 0.759; Ser,Arg,Kyn,QA, 0.759; Ala,Arg,Lys,AnthA, 0.758; Ala,Cit,hTrp,Kyn, 0.758; Thr,Arg,hKyn,hTrp, 0.758; Arg,Orn,hKyn,Kyn, 0.758; Arg,hAnthA,hTrp,QA, 0.757; Arg,Lys,hAnthA,QA, 0.757; Gly,Arg,hAnthA,Kyn, 0.757; Arg,hKyn,hAnthA,AnthA, 0.756; Ser,Arg,hKyn,AnthA, 0.756; Ser,Gly,Arg,hKyn,0.756; Arg,hKyn,hTrp,AnthA, 0.755; Asn,Thr,Arg,QA, 0.755; Thr,Arg,hAnthA,NP, 0.754; His,Arg,hAnthA,Kyn, 0.754; Arg,hAnthA,AnthA,QA, 0.753; Arg,hTrp,AnthA,QA, 0.753; Arg,Lys,hKyn,hTrp, 0.752; Arg,hAnthA,Kyn,NP, 0.752; Gly,Arg,hKyn,hTrp, 0.752; Asn,Arg,hAnthA,QA, 0.751; Asn,Arg,hKyn,QA, 0.751; Arg,Trp,AnthA,QA, 0.751; Cit,Arg,hAnthA,Kyn, 0.75; Ser,Arg,hKyn,hAnthA, 0.75; Arg,Trp,hKyn,AnthA, 0.75; Asn,His,Arg,QA, 0.75; Cit,Arg,AnthA,Kyn, 0.749; Arg,Orn,Lys,hKyn, 0.748; His,Arg,AnthA,QA, 0.748; Ser,Arg,Lys,hKyn, 0.747; Asn,Ala,Arg,hKyn, 0.747; Ser,Cit,Arg,Kyn, 0.747; Arg,Lys,hAnthA,AnthA, 0.746; Arg,hKyn,hAnthA,hTrp, 0.746; His,Arg,hKyn,hTrp, 0.746; His,Cit,Arg,Kyn, 0.746; Ser,Asn,Arg,QA, 0.746; Ser,Arg,hAnthA,NP, 0.745; Arg,hKyn,hTrp,NP, 0.745; Ser,Cit,Arg,QA, 0.745; Cit,Arg,hKyn,QA, 0.744; Arg,AnthA,QA,NP, 0.744; Ala,Arg,AnthA,QA, 0.744; Asn,Arg,Lys,hKyn, 0.743; Ala,Arg,hAnthA,hTrp, 0.743; Ala,Arg,hAnthA,NP, 0.743; Ser,Gly,Arg,hAnthA, 0.743; Cit,Arg,AnthA,QA, 0.742; Cit,Arg,hKyn,hAnthA, 0.742; Ser,Cit,Arg,hKyn, 0.742; Gly,Ala,Arg,hAnthA, 0.742; Ser,Thr,Arg,hKyn, 0.742; Ser,Arg,Orn,hKyn, 0.741; Asn,Arg,hAnthA,AnthA, 0.74; Arg,Trp,hKyn,hTrp, 0.74; Arg,Lys,hAnthA,hTrp, 0.739; Asn,Arg,Trp,hAnthA, 0.735; Asn,Arg,hAnthA,hTrp, 0.735; Ser,Asn,Arg,hAnthA, 0.734; Ser,His,Arg,hAnthA, 0.734; Cit,Trp,hAnthA,AnthA, 0.713.

[0161] [109. Five-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment] Ser,Gly,Thr,Arg,QA, 0.797; Ser,Gly,Cit,Arg,QA, 0.782; Gly,Thr,Arg,Orn,QA, 0.779; Ser,Gly,Arg,hAnthA,QA, 0.777; Asn,Ala,Arg,Lys,Kyn, 0.777; Ser,Gly,Ala,Arg,QA, 0.776; Thr,Ala,Arg,hAnthA,Kyn, 0.775; Asn,Ala,Arg,AnthA,Kyn, 0.773; Arg,hKyn,hTrp,AnthA,Kyn, 0.773; Ala,Arg,hTrp,Kyn,NP, 0.773; Thr,Arg,hTrp,AnthA,QA, 0.772; Thr,Ala,Arg,AnthA,QA, 0.772; Ser,Arg,hAnthA,hTrp,Kyn, 0.771; Ser,Cit,Arg,hAnthA,QA, 0.771; Arg,hTrp,AnthA,Kyn,NP, 0.771; Gly,Ala,Arg,hTrp,Kyn, 0.77; Ala,Arg,hAnthA,Kyn,NP, 0.768; Asn,Arg,Lys,AnthA,Kyn, 0.768; Ser,Arg,hAnthA,Kyn,QA, 0.767; Ser,His,Arg,hAnthA,QA, 0.767; Ser,Arg,Orn,hAnthA,QA, 0.767; Ala,Cit,hAnthA,hTrp,Kyn, 0.766; Arg,Lys,hTrp,AnthA,QA, 0.766; Gly,Arg,hAnthA,hTrp,QA, 0.766; Arg,Lys,hAnthA,hTrp,Kyn, 0.765; Cit,Arg,Trp,hTrp,Kyn, 0.765; Cit,Arg,Trp,hTrp,QA, 0.765; Ser,Arg,hKyn,hAnthA,QA, 0.764; Ala,Arg,Trp,hAnthA,Kyn, 0.764; Ala,Cit,hAnthA,AnthA,QA, 0.764; Asn,His,Arg,AnthA,Kyn, 0.764; Arg, hAnthA, hTrp, AnthA, Kyn, 0.763; Asn,Ala,Arg,hKyn,AnthA,763; Ala,Arg,hAnthA,Kyn,QA, 0.763; Arg,Orn,Lys,AnthA,QA, 0.763; Asn,Arg,hKyn,hAnthA,QA, 0.763; Ser,Arg,Lys,hKyn,AnthA, 0.763; Ser,Gly,Arg,hAnthA,Kyn, 0.763; Arg,Lys,Trp,AnthA,Kyn, 0.763; Ala,Arg,Lys,AnthA,NP, 0.763; Ser,Arg,Lys,AnthA,Kyn, 0.763; Gly,Ala,Arg,Lys,hKyn, 0.762; His,Ala,Arg,Lys,hKyn, 0.762; Thr,Arg,hAnthA,QA,NP, 0.762; Thr,Arg,hAnthA,Kyn,NP, 0.762; Ser,Arg,Lys,hAnthA,QA, 0.761; Cit,Arg,Orn,hTrp,Kyn, 0.761; Thr,Arg,Trp,hAnthA,QA, 0.761; Arg,Lys,hAnthA,hTrp,QA, 0.76; Asn,Arg,hAnthA,hTrp,Kyn, 0.76; Ala, Arg, Orn, Lys, hKyn, 0.76; Arg,Trp,hKyn,hAnthA,Kyn, 0.76; His,Thr,Arg,hAnthA,Kyn, 0.76; Thr,Ala,Arg,Lys,hAnthA, 0.76; Arg,Lys,Trp,hKyn,AnthA, 0.759; Cit,Arg,Lys,hKyn,QA, 0.759; Gly,Arg,hAnthA,Kyn,QA, 0.759; Gly,Arg,Lys,hKyn,Kyn, 0.759; Ser,Gly,Arg,Trp,Kyn, 0.759; Ser,Arg,hAnthA,AnthA,NP, 0.758; Ser,Gly,Arg,hAnthA,NP, 0.758; Ser,Asn,Arg,AnthA,QA, 0.758; Ala,Cit,Arg,Kyn,QA, 0.758; Ser,Arg,Orn,hAnthA,Kyn, 0.757; Arg,Trp,hAnthA,AnthA,QA, 0.756; Thr,Ala,Arg,hAnthA,NP, 0.756; Arg,Lys,hKyn,hAnthA,hTrp, 0.755; His,Arg,hKyn,hTrp,AnthA, 0.755; Asn,Gly,Arg,hAnthA,QA, 0.754; Arg,hKyn,hAnthA,AnthA,NP, 0.754; Gly,Arg,Lys,hAnthA,QA, 0.754; Ser,Arg,hKyn,hTrp,QA, 0.754; Arg,Orn,hKyn,hAnthA,AnthA, 0.754; Ser,Arg,Lys,hKyn,hTrp, 0.754; Arg,hAnthA,AnthA,Kyn,NP, 0.753; Arg,Lys,Trp,hKyn,QA, 0.753; Ala,Arg,Orn,hAnthA,QA, 0.753; Ser,His,Arg,hAnthA,NP, 0.752; Asn,Arg,Trp,hAnthA,Kyn, 0.751; Asn,Arg,Lys,hAnthA,QA, 0.751; Cit,Arg,hKyn,hAnthA,hTrp, 0.751; Ser,Cit,Arg,hTrp,QA, 0.751; Arg,Orn,Lys,hKyn,QA, 0.751; Thr,Arg,Lys,hAnthA,NP, 0.751; Asn,Ala,Arg,hAnthA,hTrp, 0.75; Ser,His,Arg,Lys,hKyn, 0.75; Ser,Arg,Lys,hKyn,hAnthA, 0.749; Arg,Lys,hKyn,hAnthA,QA, 0.748; Arg,Lys,Trp,hKyn,hTrp, 0.748; Ala,Arg,Trp,hAnthA,AnthA, 0.747; Ser,Ala,Arg,hAnthA,hTrp, 0.747; Ser,Arg,Orn,hAnthA,AnthA, 0.747; Ser,Gly,Arg,hKyn,hAnthA, 0.746; Ser,Gly,Arg,Trp,hAnthA, 0.746; Ser,Gly,Arg,hAnthA,hTrp, 0.746; Arg,Lys,Trp,hKyn,hAnthA, 0.746; Asn,Thr,Ala,Arg,hAnthA, 0.745; Ser,Asn,Ala,Arg,hAnthA, 0.738; Asn,Arg,Trp,hKyn,hAnthA, 0.738; Cit,Trp,hKyn,hAnthA,AnthA, 0.738.

[0162] [110. Equation of six variables derived from amino acids and amino acid-related metabolites before the start of treatment] Ser,Asn,Gly,His,Arg,QA, 0.804; Ser,Asn,Gly,Arg,hTrp,QA, 0.796; Ser,Gly,Arg,Lys,hTrp,QA, 0.795; Ser,Asn,Gly,Thr,Arg,QA, 0.793; Asn,Gly,Thr,Ala,Arg,QA, 0.791; Thr,Ala,Arg,Lys,AnthA,QA, 0.79; Asn,Gly,Thr,Cit,Arg,QA, 0.789; Ser,Gly,Thr,Arg,hAnthA,QA, 0.788; Asn,Thr,Ala,Arg,hTrp,Kyn, 0.788; Ser,Asn,Ala,Arg,hAnthA,Kyn, 0.786; Gly,Thr,Arg,hAnthA,hTrp,QA, 0.786; Ser,Asn,Gly,Arg,Kyn,QA, 0.786; Ser,Gly,Arg,hAnthA,hTrp,QA, 0.785; Ser,Asn,Gly,Arg,QA,NP, 0.785; Ser,Asn,Gly,Arg,hAnthA,QA, 0.783; Ser,Gly,Ala,Arg,Kyn,QA, 0.783; Ser,Gly,His,Arg,Lys,QA, 0.783; Ser,Gly,Arg,Orn,Lys,QA, 0.783; Ser,Gly,His,Arg,hTrp,QA, 0.782; Ser,Ala,Arg,hAnthA,Kyn,QA, 0.781; Thr,Arg,Lys,Trp,AnthA,Kyn, 0.781; Ser,Gly,Cit,Arg,hAnthA,QA, 0.78; Ser,Arg,hKyn,hAnthA,hTrp,QA, 0.78; Asn,Ala,Arg,Lys,AnthA,Kyn, 0.779; Ser,Gly,Ala,Arg,hAnthA,QA, 0.779; Gly,Thr,Arg,hAnthA,AnthA,QA, 0.779; Asn,Thr,Arg,hTrp,AnthA,QA, 0.779; Ser,Gly,Arg,hKyn,hAnthA,QA, 0.779; Ser,Gly,Arg,hAnthA,QA,NP, 0.779; Asn,Ala,Arg,hAnthA,AnthA,NP, 0.<h2 style=";text-align:left;direction:ltr">779; Asn,Ala,Arg,hAnthA,Kyn,NP, 0.779; Ser,Ala,Arg,hKyn,hAnthA,Kyn, 0.779; Asn,Gly,Ala,Cit,Arg,QA, 0.779; Asn,Arg,hTrp,AnthA,Kyn,QA, 0.779; Ser,Arg,hAnthA,hTrp,AnthA,QA, 0.778; Asn,Ala,Arg,AnthA,Kyn,NP, 0.778; Ser,Gly,Arg,Trp,hAnthA,QA, 0.777; Ala,Cit,Arg,Lys,hTrp,Kyn, 0.777; Ser,His,Arg,hAnthA,hTrp,QA, 0.777; Ser,His,Ala,Arg,hAnthA,Kyn, 0.777; Asn,Cit,Arg,hTrp,Kyn,QA, 0.777; Thr,Arg,hKyn,hTrp,AnthA,QA, 0.777; Ser,Gly,Arg,hAnthA,Kyn,QA, 0.776; Ser,Gly,Arg,Lys,hAnthA,QA, 0.776; Ser,Arg,Orn,hAnthA,hTrp,QA, 0.776; Asn,Ala,Arg,hTrp,AnthA,QA, 0.776; Ala,Cit,Arg,Lys,Kyn,QA, 0.776; Asn,Ala,Arg,Lys,AnthA,QA, 0.774; Thr,Ala,Arg,Lys,hAnthA,NP, 0.774; Ala,Arg,Lys,hAnthA,hTrp,Kyn, 0.773; Gly,Ala,Arg,Lys,Kyn,QA, 0.773; Ala,Cit,Arg,Lys,Kyn,NP, 0.773; Thr,Ala,Arg,Lys,hKyn,QA, 0.773; Asn,Cit,Arg,AnthA,Kyn,QA, 0.773; Asn,His,Arg,hAnthA,AnthA,Kyn, 0.772; Gly,Ala,Arg,Lys,hAnthA,Kyn, 0.771; Thr,Arg,Lys,AnthA,Kyn,QA, 0.771; Gly,Ala,Cit,Arg,Lys,Kyn, 0.771; Ser,Arg,Lys,hTrp,Kyn,QA, 0.771; Arg, Orn, Light, Trp, AnthA, Kyn, 0.771; Ala,Cit,Arg,Lys,hAnthA,Kyn, 0.771; Ser,Arg,hAnthA,AnthA,Kyn,QA, 0.771; Asn,Ala,Arg,hKyn,AnthA,QA, 0.771; His, Thr, Arg, Light, hTrp, QA, 0.768; Gly,His,Ala,Arg,Lys,Kyn, 0.767; His,Ala,Arg,Lys,AnthA,QA, 0.766; Asn,His,Cit,Arg,hAnthA,QA, 0.766; Arg,Orn,Lys,hKyn,AnthA,NP, 0.766; Arg,Lys,Trp,hKyn,hAnthA,AnthA, 0.765; Ser,Ala,Arg,hAnthA,AnthA,NP, 0.765; Ser,Ala,Arg,Orn,hAnthA,QA, 0.765; Thr,Ala,Cit,hAnthA,hTrp,Kyn, 0.765; Arg,Lys,hAnthA,hTrp,Kyn,NP, 0.765; Thr,Arg,Lys,hKyn,hAnthA,AnthA, 0.764; Ser,Arg,Orn,hAnthA,AnthA,Kyn, 0.764; His,Arg,hAnthA,hTrp,AnthA,QA, 0.763; Ser,Arg,Orn,hAnthA,hTrp,NP, 0.763; Asn,Arg,Trp,hKyn,AnthA,NP, 0.763; Arg,Lys,hAnthA,AnthA,Kyn,QA, 0.763; Cit, Arg, Lys, hKyn, hTrp, AnthA, 0.763; Asn,Ala,Arg,Lys,AnthA,NP, 0.763; Gly, Arg, Lys, hKyn, AnthA, NP, 0.763; Arg,Lys,Trp,hKyn,hTrp,AnthA, 0.762; Cit, Arg, hAnthA, hTrp, AnthA, Kyn, 0.762; Gly,Arg,hAnthA,hTrp,AnthA,QA, 0.762; Ala,Cit,Trp,hAnthA,hTrp,Kyn, 0.761; Thr,Ala,Arg,hAnthA,AnthA,NP,761; His, Arg, Lys, hKyn, hTrp, AnthA, 0.76; Gly,Arg,Lys,Trp,hKyn,AnthA, 0.759; Arg, Orn, hAnthA, AnthA, Kyn, QA, 0.759; Arg,Lys,Trp,hAnthA,AnthA,Kyn, 0.758; Cit,Arg,hKyn,hAnthA,hTrp,QA, 0.757; Ala,Arg,Orn,hAnthA,AnthA,QA, 0.757; Ser,Cit,Arg,hAnthA,Kyn,NP, 0.756; Ser,Gly,Ala,Arg,hAnthA,NP, 0.756; Ala,Cit,Arg,hAnthA,hTrp,AnthA, 0.754; Ala, Arg, Orn, hAnthA, hTrp, AnthA, 0.754; Asn,Arg,Trp,hKyn,hAnthA,Kyn, 0.754; Asn,Thr,Arg,Trp,hAnthA,AnthA, 0.753; Asn,His,Arg,Lys,hKyn,AnthA, 0.752.

[0163] [111.2-year-old snowflake snowflakes] Leu,Phe, 0.783; Orn, Trp, 0.783; Val, Phe, 0.767; Met, Phe, 0.758; Phe,Trp, 0.754; Val, Orn, 0.749; Serum, Wave, 0.749; Pro, Wave, 0.747; Asn, Wave, 0.747; Ala, Val, 0.743; Cit, Val, 0.741; Wave, Trp, 0.741; Gly, Val, 0.741; Tyr, Val, 0.741; Glu, Val, 0.741; Wave, Met, 0.741; Arg, Val, 0.737; Cit,Trp, 0.737; Gln, Wave, 0.737; Orn, Leo, 0.737; ABA, Wave, 0.735; His,Phe, 0.735; Asn,Leu, 0.733; Arg,Leu, 0.73; Arg,Trp, 0.73; Val,Ile, 0.73; Ser,Leu, 0.73; His,Orn, 0.728; Thr,Cit, 0.726; Ile,Phe, 0.726; Leu,Trp, 0.726; Gly,Leu, 0.726; Cit,Leu, 0.724; Val,Lys, 0.72; Met,Orn, 0.72; Arg,Orn, 0.718; Arg,ABA, 0.718; Ile,Trp, 0.716; Gln,Leu, 0.716; Ala,Leu, 0.716; ABA,Leu, 0.716; Thr,Val, 0.715; His,Val, 0.715; Lys,Trp, 0.715; His,Leu, 0.715; Lys,Leu, 0.715; Thr,Trp, 0.713; Val,Leu, 0.713; Thr,Leu, 0.713; Thr,Orn, 0.711; Asn,Arg, 0.711; His,Cit, 0.711; Ile,Leu, 0.711; Glu,Leu, 0.711; Arg,Met, 0.709; Pro,Leu, 0.709; Cit,Tyr, 0.707; Tyr,Leu, 0.707; Thr,Phe, 0.705; His,Trp, 0.703; Asn,Trp, 0.703; Arg,Ile, 0.701; Cit,Arg, 0.701; Cit,Met, 0.701; Glu,Trp, 0.699; Pro,Trp, 0.699; His,Ile, 0.699; His,Thr, 0.698; His,Arg, 0.698; Met,Leu, 0.698; Gly,Trp, 0.696; Ser,Trp, 0.696; Gln,Trp, 0.696; Ala,Trp, 0.694; Met,Trp, 0.694; Thr,Ile, 0.694; ABA,Trp, 0.692; Tyr,Trp, 0.692; Thr,Ala, 0.692; Glu,Arg, 0.69; 0.69; Thr,Lys, 0.69; Thr,Met, 0.69; Arg,Pro, 0.69; Cit,ABA, 0.69; Gln,Thr, 0.688; Thr,Tyr, 0.688; Cit,Ile, 0.688; Thr,Pro, 0.686; 0.682; Glu,Thr, 0.682; Thr,ABA, 0.682; Arg,Lys, 0.682; Asn,Thr, 0.681; Ser,Arg, 0.679; Gly,Thr, 0.679; Gly,Arg, 0.677; Ser,Thr, 0.669.

[0164] [112. Three-variable equation obtained from amino acids after the start of treatment] Orn,Leu,Phe, 0.832; Cyt,Leu,Phe, 0.813; Arg,Leu,Phe, 0.803; Pro,Leu,Phe, 0.802; Gly,Leu,Phe, 0.798; Ile,Leu,Phe, 0.796; Val,Leu,Phe, 0.794; Lys,Leu,Phe, 0.794; Val,Orn,Phe, 0.792; Orn,Leu,Trp, 0.792; Glu,Leu,Phe, 0.79; Gly,Orn,Trp, 0.79; Arg,Phe,Trp, 0.79; Pro,Val,Phe, 0.788; Ser,Leu,Phe, 0.788; Tyr,Orn,Trp, 0.788; His,Leu,Phe, 0.786; Thr,Leu,Phe, 0.786; Ala, Orn, Trp, 0.786; Cit, Orn, Trp, 0.786; Orn, Phe, Trp, 0.784; Gln, Orn, Trp, 0.784; Val,Phe,Trp, 0.783; Asn,Leu,Phe, 0.783; Met, Orn, Trp, 0.783; Arg, Orn, Trp, 0.783; Asn, Orn, Trp, 0.783; ABA, Orn, Trp, 0.783; Cit,Val,Phe, 0.781; ABA,Leu,Phe, 0.781; Pro, Orn, Trp, 0.781; Serum, Orn, Trp, 0.781; Arg, Val, Phe, 0.779; His, Orn, Trp, 0.779; Val,Met,Phe, 0.777; Cyt,Phe,Trp, 0.777; Thr,Orn,Trp, 0.777; Tyr, Val, Phe, 0.773; Val, Lys, Phe, 0.771; Wave, Orn, Trp, 0.771; Thr,Phe,Trp, 0.769; Glu,Val,Phe, 0.767; Ala, Val, Phe, 0.767; Serum, Val, Phe, 0.767; Asn, Val, Phe, 0.767; Gln, Phe, Trp, 0.767; Ser, Phe, Trp, 0.766; Lys, Phe, Trp, 0.764; Gln, Orn, Leo, 0.764; Val, Ile, Phe, 0.76; Arg, Val, Orn, 0.76; Pro,Val,Orn, 0.76; Arg, ABA, Phe, 0.76; Tyr, Phe, Trp, 0.758; Cit,Met,Phe, 0.758; Val, Orn, Lys, 0.758; His, Ile, Phe, 0.756; Tyr, Val, Orn, 0.756; Pro,Phe,Trp, 0.754; Asn, Phe, Trp, 0.754; His, Phe, Trp, 0.752; Cit,Val,Trp, 0.752; Thr,Val,Orn, 0.752; Gly,Cyt,Val, 0.752; Arg,Pro,Val, 0.75; Val, Orn, Ile, 0.75; Gly, Val, Orn, 0.75; Arg, Orn, Leo, 0.749; Cit, Val, Orn, 0.749; Cit,Arg,Leu, 0.749; Glu,Cit,Val, 0.749; Serum,Cit,Val, 0.747; Val, Orn, Leo, 0.747; Ala, Val, Orn, 0.747; Ser, Val, Orn, 0.745; Cit, Val, Ile, 0.745; Arg,Val,Trp, 0.745; Ser,Cit,Leu, 0.743; Cit, Lys, Trp, 0.743; Cit,Pro,Trp, 0.743; Arg, Val, Lys, 0.741; Thr,Cyt,Val, 0.741; Asn, Arg, Leu, 0.741; Thr, Cyt, Phe, 0.737; Thr,Orn,Leu, 0.737; Arg,Val,Ile, 0.737; Arg,ABA,Orn, 0.737; Glu,Cit,Trp, 0.735; Gln,Cit,Trp, 0.733; Asn,Cit,Trp, 0.732; Arg,Val,Met, 0.73; Arg,Pro,Leu, 0.728; Arg,Lys,Leu, 0.726; Thr,Cit,Arg, 0.726; Gly,Arg,Leu, 0.724; Arg,Met,Leu, 0.724; Ser,Arg,Leu, 0.722; Glu,Arg,Val, 0.72; Glu,Arg,Trp, 0.72; Glu,Arg,Leu, 0.705.

[0165] [113. Four-variable equation obtained from amino acids after the start of treatment] Gln,Orn,Leu,Phe, 0.834; Val,Orn,Leu,Phe, 0.832; Met,Orn,Leu,Phe, 0.83; Cit,Pro,Leu,Phe, 0.828; Arg,Orn,Leu,Phe, 0.828; Arg,Pro,Leu,Phe, 0.824; Cit,Orn,Leu,Phe, 0.82; Cit,Lys,Leu,Phe, 0.82; Cit,ABA,Leu,Phe, 0.817; Cit,Tyr,Leu,Phe, 0.815; Cit,Met,Leu,Phe, 0.813; Cit,Val,Leu,Phe, 0.813; Pro,Leu,Phe,Trp, 0.813; Pro,Lys,Leu,Phe, 0.811; Arg,Ile,Leu,Phe, 0.809; Cit,Ile,Leu,Phe, 0.809; Asn,Cit,Leu,Phe, 0.809; Glu,Cit,Leu,Phe, 0.809; Ala,Pro,Leu,Phe, 0.807; Arg,Leu,Phe,Trp, 0.805; Arg,ABA,Leu,Phe, 0.805; Pro,Ile,Leu,Phe, 0.805; Asn,Pro,Leu,Phe, 0.805; Pro,Tyr,Leu,Phe, 0.805; Pro,Val,Phe,Trp, 0.805; Gly,Orn,Phe,Trp, 0.803; Glu,Pro,Leu,Phe, 0.803; Val,Met,Orn,Phe, 0.803; Thr,Met,Leu,Phe, 0.803; Arg,Lys,Leu,Phe, 0.802; Gln,Arg,Leu,Phe, 0.802; Pro,Tyr,Val,Phe, 0.802; Val,Met,Leu,Phe, 0.802; Arg,Tyr,Leu,Phe, 0.8; Gln,Lys,Leu,Phe, 0.8; Ala,Met,Leu,Phe, 0.8; Gly,Met,Leu,Phe, 0.8; Asn,Arg,Leu,Phe, 0.798; Gln,Pro,Leu,Phe, 0.798; Gly,Pro,Leu,Phe, 0.798; Gln,Val,Leu,Phe, 0.798; Glu,Gly,Leu,Phe, 0.798; Gly,Lys,Leu,Phe, 0.798; Glu,Asn,Leu,Phe, 0.798; Gly,Ala,Leu,Phe, 0.798; Pro,Val,Orn,Phe, 0.796; Orn,Ile,Phe,Trp, 0.796; Gln,Ala,Leu,Phe, 0.796; Tyr,Val,Leu,Phe, 0.796; ABA,Lys,Leu,Phe, 0.796; Glu,Gln,Leu,Phe, 0.794; Tyr,Lys,Leu,Phe, 0.794; Ile,Leu,Phe,Trp, 0.792; Asn,Val,Orn,Phe, 0.792; His,Met,Leu,Phe, 0.792; Thr,Lys,Leu,Phe, 0.792; Tyr,Orn,Lys,Trp, 0.792; Ser,Orn,Phe,Trp, 0.79; Ser,Pro,Val,Phe, 0.79; Cit,Val,Orn,Phe, 0.79; Gly,Gln,Leu,Phe, 0.79; Gln,Val,Orn,Phe, 0.79; Cit,ABA,Val,Phe, 0.79; Glu,His,Leu,Phe, 0.79; Ala,Ile,Leu,Phe, 0.79; Cit,Pro,Val,Phe, 0.788; Val,Orn,Lys,Phe, 0.788; His,Arg,Val,Phe, 0.788; Gln,Val,Phe,Trp, 0.788; Tyr,Ile,Leu,Phe, 0.788; Ser,Lys,Leu,Phe, 0.788; Thr, Tyr, Leu, Phe, 0.788; Serum, Tyr, Val, Phe, 0.788; Lys, Ile, Leu, Phe, 0.786; His, Lys, Leu, Phe, 0.786; Gln, Orn, Lys, Trp, 0.786; Glu, Val, Phe, Trp, 0.784; Asn, Val, Phe, Trp, 0.784; ABA, Tyr, Leu, Phe, 0.784; Asn, ABA, Leu, Phe, 0.784; Tyr, Orn, Phe, Trp, 0.783; Orn, Lys, Leu, Trp, 0.783; Glu, Asn, Val, Phe, 0.783; Asn, Tyr, Leu, Phe, 0.781; Cit,Val,Lys,Phe, 0.779; Ala,Arg,Val,Phe, 0.779; Arg,Val,Met,Phe, 0.779; His,Tyr,Val,Phe, 0.779; Gln,Tyr,Val,Phe, 0.779; Asn,Pro,Val,Phe, 0.777; Ser,Val,Met,Phe, 0.777; Gly,Val,Met,Phe, 0.775; Gly,Thr,Val,Phe, 0.773; Ser,Thr,Val,Phe, 0.773; Val,Met,Ile,Phe, 0.773; Gln,Thr,Val,Phe, 0.773; His,Val,Lys,Phe, 0.769; Thr,Ala,Val,Phe, 0.767; Gly,Val,Lys,Phe, 0.76; Ala,Val,Ile,Phe, 0.76.

[0166] [114.You cannot be afraid to talk] Arg,Orn,Leu,Phe,Trp, 0.853; Gln,Pro,Orn,Leu,Phe, 0.847; Thr,Arg,Pro,Leu,Phe, 0.843; Pro,Orn,Leu,Phe,Trp, 0.839; Pro,Tyr,Orn,Leu,Phe, 0.839; Ser,Pro,Orn,Leu,Phe, 0.839; Val,Orn,Leu,Phe,Trp, 0.837; Pro,Val,Orn,Leu,Phe, 0.837; Asn,Pro,Orn,Leu,Phe, 0.837; Pro,Orn,Lys,Leu,Phe, 0.836; Gln,His,Orn,Leu,Phe, 0.836; Ala,Arg,Orn,Leu,Phe, 0.834; Ser,Thr,Orn,Leu,Phe, 0.834; Cit,Pro,Orn,Leu,Phe, 0.832; Ala,Orn,Ile,Leu,Phe, 0.832; Arg,Pro,Orn,Leu,Phe, 0.83; Thr,Arg,Orn,Leu,Phe, 0.83; Arg,Orn,Ile,Leu,Phe, 0.828; Cit,Arg,Pro,Leu,Phe, 0.828; Val,Orn,Lys,Leu,Phe, 0.828; Cit,Pro,Ile,Leu,Phe, 0.826; Arg,Met,Orn,Leu,Phe, 0.826; Cit,Arg,Orn,Leu,Phe, 0.826; Gln,Arg,Pro,Leu,Phe, 0.824; Ser,Pro,Leu,Phe,Trp, 0.824; Cit,Pro,Tyr,Leu,Phe, 0.822; Ser,Cit,Orn,Leu,Phe, 0.822; Arg,Pro,Val,Leu,Phe, 0.82; His,Arg,Pro,Leu,Phe, 0.82; Ser,Cit,Pro,Leu,Phe, 0.82; Met,Orn,Lys,Leu,Phe, 0.82; Cit,Val,Orn,Leu,Phe, 0.82; His,Val,Orn,Leu,Phe, 0.82; Thr,Pro,Leu,Phe,Trp, 0.819; Arg,Pro,Leu,Phe,Trp, 0.817; Gln,Cit,Leu,Phe,Trp, 0.817; Arg,Pro,Met,Leu,Phe, 0.815; Cit,Arg,Leu,Phe,Trp, 0.815; Cit,Arg,Met,Leu,Phe, 0.815; His,Ala,Orn,Leu,Phe, 0.815; Asn,Pro,Leu,Phe,Trp, 0.815; His,Cit,Lys,Leu,Phe, 0.815; Ser,Tyr,Leu,Phe,Trp, 0.815; Gln,Val,Orn,Phe,Trp, 0.813; Ala,Val,Orn,Phe,Trp, 0.813; Gln,Cit,Lys,Leu,Phe, 0.813; Ala,Pro,Met,Leu,Phe, 0.813; Cit,Met,Leu,Phe,Trp, 0.811; Ser,Cit,Lys,Leu,Phe, 0.811; Gly,His,Cit,Leu,Phe, 0.811; Arg,Ile,Leu,Phe,Trp, 0.809; Glu,Ser,Cit,Leu,Phe, 0.809; Asn,Thr,Cit,Leu,Phe, 0.809; Cit,Val,Lys,Leu,Phe, 0.809; ABA,Tyr,Leu,Phe,Trp, 0.809; Ser,ABA,Leu,Phe,Trp, 0.809; Gln,Lys,Leu,Phe,Trp, 0.807; His,ABA,Leu,Phe,Trp, 0.807; Pro,Tyr,Val,Leu,Phe, 0.807; Ala,Arg,ABA,Leu,Phe, 0.805; Gly,Lys,Leu,Phe,Trp, 0.805; Pro,ABA,Tyr,Leu,Phe, 0.805; Asn,Pro,ABA,Leu,Phe, 0.805; Glu,His,Leu,Phe,Trp, 0.803; Ala,Arg,Val,Orn,Phe, 0.803; Ser,Arg,Val,Orn,Phe, 0.803; Gln,Ala,Met,Leu,Phe, 0.803; Cit,Val,Ile,Leu,Phe, 0.802; Asn,His,Arg,Leu,Phe, 0.802; Thr,Ile,Leu,Phe,Trp, 0.802; Ser,Gly,Orn,Phe,Trp, 0.802; Gln,Pro,Val,Leu,Phe, 0.802; Glu,Pro,Tyr,Leu,Phe, 0.802; Tyr,Ile,Leu,Phe,Trp, 0.8; Gln,Pro,Ile,Leu,Phe, 0.8; Glu,Asn,Val,Orn,Phe, 0.8; Arg,Pro,Val,Ile,Phe, 0.798; Ser,ABA,Orn,Phe,Trp, 0.798; Glu,Arg,Ile,Leu,Phe, 0.796; His,Pro,Val,Orn,Phe, 0.796; Tyr,Met,Ile,Leu,Phe, 0.796; Gly,ABA,Val,Orn,Phe, 0.796; Ser,Ala,Orn,Phe,Trp, 0.794; Ser,Met,Ile,Leu,Phe, 0.794; His,Arg,Tyr,Leu,Phe, 0.792; Ser,Cit,Orn,Phe,Trp, 0.792; Ser,Asn,Orn,Phe,Trp, 0.792; Cit,Pro,Val,Ile,Phe, 0.79; Thr,Tyr,Val,Orn,Phe, 0.79; Arg,Tyr,Orn,Phe,Trp, 0.786; His,Arg,Val,Lys,Phe, 0.786; Gly,Tyr,Val,Orn,Phe, 0.786; Tyr,Val,Ile,Leu,Phe, 0.786; Asn,His,Cit,Val,Phe, 0.784; Glu,Arg,Met,Leu,Phe, 0.783; Orn,Lys,Ile,Phe,Trp, 0.783; Glu,Arg,Tyr,Leu,Phe, 0.781; Ser,Gln,Cit,Val,Phe, 0.779; Gly,Gln,Arg,Val,Phe, 0.777; Asn,Gln,Cit,Val,Phe, 0.777.

[0167] [115.What is the meaning of the words] Arg,Orn,Lys,Leu,Phe,Trp, 0.854; Thr,Orn,Lys,Leu,Phe,Trp, 0.853; Ser,Val,Orn,Leu,Phe,Trp, 0.847; Ala,Pro,Orn,Leu,Phe,Trp, 0.845; Pro,ABA,Orn,Ile,Leu,Phe, 0.843; Ala,Pro,Tyr,Orn,Leu,Phe, 0.843; Thr,Ala,Pro,Orn,Leu,Phe, 0.843; Pro,Tyr,Orn,Leu,Phe,Trp, 0.841; Ala,Pro,Val,Orn,Leu,Phe, 0.841; Glu,Met,Orn,Ile,Leu,Phe, 0.837; Glu,Cit,Arg,Pro,Leu,Phe, 0.836; Cit,Arg,Pro,Orn,Leu,Phe, 0.836; Glu,Thr,Pro,Orn,Leu,Phe, 0.836; Gln,Orn,Ile,Leu,Phe,Trp, 0.834; Ser,Ala,Orn,Leu,Phe,Trp, 0.834; Thr,Ala,Orn,Ile,Leu,Phe, 0.834; Gln,Arg,Pro,Orn,Leu,Phe, 0.832; Cit,Arg,Pro,Ile,Leu,Phe, 0.832; Ala,Arg,Pro,Orn,Leu,Phe, 0.832; Glu,Gly,Cit,Pro,Leu,Phe, 0.832; Gln,Pro,Orn,Ile,Leu,Phe, 0.832; Thr,Cit,Arg,Orn,Leu,Phe, 0.832; Asn,Gly,Arg,Orn,Leu,Phe, 0.832; Glu,Pro,ABA,Orn,Leu,Phe, 0.832; His,Orn,Ile,Leu,Phe,Trp, 0.83; Arg,Pro,Orn,Leu,Phe,Trp, 0.83; Cit,Arg,Pro,Met,Leu,Phe, 0.83; Cit,Pro,ABA,Orn,Leu,Phe, 0.83; Asn,Arg,ABA,Orn,Leu,Phe, 0.83; Gly,Arg,Pro,Orn,Leu,Phe, 0.828; Gly,Cit,Arg,Pro,Leu,Phe, 0.828; Asn,Cit,Arg,Pro,Leu,Phe, 0.828; Cit,Arg,Pro,Leu,Phe,Trp, 0.828; Glu,Asn,Cit,Pro,Leu,Phe, 0.828; Arg,Pro,ABA,Orn,Leu,Phe, 0.826; His,Arg,Pro,Orn,Leu,Phe, 0.826; Cit,Arg,Pro,Tyr,Leu,Phe, 0.826; Glu,Cit,Pro,Ile,Leu,Phe, 0.826; Gln,Arg,Pro,Leu,Phe,Trp, 0.826; Cit,Pro,ABA,Met,Leu,Phe, 0.826; Asn,Cit,Pro,Ile,Leu,Phe, 0.826; Thr,Ala,Cit,Pro,Leu,Phe, 0.826; Cit,Pro,Orn,Lys,Leu,Phe, 0.826; Glu,Cit,Arg,Orn,Leu,Phe, 0.826; Glu,Arg,Pro,Orn,Leu,Phe, 0.824; Cit,Arg,Pro,Lys,Leu,Phe, 0.824; Ser,Cit,Pro,Met,Leu,Phe, 0.824; Glu,Ser,Cit,Pro,Leu,Phe, 0.824; Asn,Cit,Arg,Ile,Leu,Phe, 0.824; Glu,Arg,ABA,Orn,Leu,Phe, 0.824; Ala,Cit,Pro,Leu,Phe,Trp, 0.822; Glu,His,Cit,Pro,Leu,Phe, 0.822; Thr,Cit,Pro,Val,Leu,Phe, 0.822; Ser,Thr,Cit,Pro,Leu,Phe, 0.822; Thr,Arg,Val,Orn,Leu,Phe, 0.822; Ser,His,Arg,Orn,Leu,Phe, 0.822; Glu,Cit,Pro,Leu,Phe,Trp, 0.82; Gln,Arg,Pro,Ile,Leu,Phe, 0.82; Ala,Arg,Orn,Lys,Leu,Phe, 0.82; Arg,Pro,ABA,Tyr,Leu,Phe, 0.82; Glu,Gly,Thr,Arg,Leu,Phe, 0.82; Glu,Gln,Arg,Pro,Leu,Phe, 0.819; Glu,Cit,Arg,Ile,Leu,Phe, 0.819; Glu,Cit,Arg,Leu,Phe,Trp, 0.819; Ala,Arg,Pro,Leu,Phe,Trp, 0.817; Ser,Arg,Tyr,Orn,Leu,Phe, 0.817; Glu,Cit,Arg,ABA,Leu,Phe, 0.817; His,Arg,Pro,Lys,Leu,Phe, 0.815; Arg,Pro,Met,Lys,Leu,Phe, 0.815; Arg,Pro,Met,Ile,Leu,Phe, 0.815; Gly,Cit,Pro,Leu,Phe,Trp, 0.815; Glu,Cit,Pro,Val,Leu,Phe, 0.815; Thr,Arg,Tyr,Lys,Leu,Phe, 0.815; Glu,Arg,Pro,ABA,Leu,Phe, 0.813; Gly,Cit,Met,Ile,Leu,Phe, 0.813; Glu,Ala,Cit,Arg,Leu,Phe, 0.813; His,Cit,Pro,Val,Phe,Trp, 0.811; Glu,Cit,ABA,Ile,Leu,Phe, 0.809; Gln,Cit,Lys,Ile,Leu,Phe, 0.809; His,Ala,Cit,Leu,Phe,Trp, 0.809; Glu,Arg,Pro,Met,Leu,Phe, 0.805; Gly,His,Arg,Ile,Leu,Phe, 0.805; Glu,Arg,Pro,Leu,Phe,Trp, 0.803; Glu,Thr,Cit,Arg,Leu,Phe, 0.803; Glu,His,Cit,Arg,Leu,Phe, 0.803; Gly,Cit,Lys,Ile,Leu,Phe, 0.803; Gln,Arg,Pro,Val,Ile,Phe, 0.802; Gly,His,Arg,Tyr,Leu,Phe, 0.802; Gln,Arg,ABA,Ile,Leu,Phe, 0.8; Asn,Ala,Cit,Pro,Val,Phe, 0.8; Glu,Cit,Arg,Met,Leu,Phe, 0.798; Gly,Cit,Pro,Val,Phe,Trp, 0.796; Asn,Ala,Orn,Lys,Phe,Trp, 0.796; Ser,Arg,Val,Lys,Leu,Phe, 0.796; His,Arg,ABA,Ile,Leu,Phe, 0.792; Glu,Ala,Arg,Ile,Leu,Phe, 0.792; Glu,Cit,Arg,Pro,Val,Phe, 0.79; Gly,Cit,Pro,Val,Orn,Phe, 0.79; Thr,Cit,Pro,Val,Ile,Phe, 0.79; Cit,Pro,ABA,Val,Ile,Phe, 0.788.

[0168] [116. Two-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment] Trp,Kyn, 0.8; Val,Kyn, 0.788; Leu,hKyn, 0.788; Leu,NP, 0.788; AnthA,NP, 0.786; Val,NP, 0.786; Cit,NP, 0.784; Leu,Kyn, 0.784; Leu,AnthA, 0.784; Orn,Trp, 0.783; Orn,NP, 0.781; Val,hKyn, 0.781; Ile,Kyn, 0.781; Also, QA, 0.779; AnthA,QA, 0.777; Leu,QA, 0.777; Thr,Kyn, 0.777; ABA,QA, 0.777; hKyn,XA, 0.777; Met,Kyn, 0.773; Arg,NP, 0.773; Thr,NP, 0.773; Val,QA, 0.771; Ile,AnthA, 0.769; Cit,Kyn, 0.769; Val,AnthA, 0.767; QA,NP, 0.766; QA,XA, 0.764; Family,QA, 0.762; XA,NP, 0.762; Met,QA, 0.76; hKyn,NP, 0.758; Family,NP, 0.756; His,Kyn, 0.756; Trp,QA, 0.754; Kyn,NP, 0.754; Orn,QA, 0.754; Thr,AnthA, 0.752; Trp,NP, 0.752; ABA,NP, 0.752; Thr,QA, 0.75; Trp,hKyn, 0.75; Asn,NP, 0.75; Arg,Kyn, 0.749; Val,Orn, 0.749; Cit,hKyn, 0.749; Ser,Val, 0.749; Gln,NP, 0.747; ABA,Kyn, 0.747; His,hKyn, 0.745; Tyr,AnthA, 0.743; Asn,QA, 0.743; Ser,NP, 0.743; Ala,NP, 0.743; Tyr,NP, 0.743; Lys,NP, 0.743; Kyn,XA, 0.743; Asn,hKyn, 0.743; Trp,AnthA, 0.741; hKyn,AnthA, 0.741; Cit,Val, 0.741; Val,Trp, 0.741; Tyr,Val,741; Arg,QA, 0.739; Tyr,QA, 0.739; Lys,QA, 0.739; Met,NP, 0.739; His,QA, 0.737; Arg,Val, 0.737; Cit,Trp, 0.737; Ile,hKyn, 0.737; Gln,Val, 0.737; Orn,Leu, 0.737; His,NP, 0.735; Val,XA, 0.732; Arg,Leu, 0.73; Thr,hKyn, 0.73; Arg,Trp, 0.73; Val,Ile, 0.73; Met,hKyn, 0.728; Thr,Cit, 0.726; 0.726; Kyn,QA, 0.726; Cit,Leu, 0.724; hKyn,QA, 0.722; Ser,QA, 0.72; Arg,hKyn, 0.718; Arg,Orn, 0.718; Arg,AnthA, 0.715; Ala,QA, 0.715; Thr,Val, 0.715; His,Val, 0.715; Thr,Trp, 0.713; Val,Leu, 0.713; Gln,QA, 0.711; Thr,Orn, 0.711; Asn,Arg, 0.711; Thr,Arg, 0.709; AnthA,Kyn, 0.709; Arg,Ile, 0.701.

[0169] [117. Three-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment] ABA,Orn,QA, 0.83; Orn,Trp,Kyn, 0.82; Orn,Trp,QA, 0.813; Cit,Val,Kyn, 0.813; Leu,AnthA,Kyn, 0.809; Also,Leu,QA, 0.807; Cit,Tyr,QA, 0.807; Orn,Trp,NP, 0.807; Similarly, ABA, QA, 0.805; Val,hKyn,AnthA, 0.805; Orn,Leu,hKyn, 0.805; Ile,AnthA,Kyn, 0.803; Ile,Trp,Kyn, 0.803; Trp,AnthA,Kyn, 0.802; Val,Orn,Kyn, 0.802; Leu,Kyn,NP, 0.802; Cit,AnthA,NP, 0.802; Leu,AnthA,NP, 0.802; Val,AnthA,Kyn, 0.8; Val,Trp,Kyn, 0.8; Also, Family, QA, 0.8; Trp,Kyn,XA, 0.8; For example, hKyn,NP, 0.8; Cit,Val,NP, 0.8; How,Tyr,Type, 0.8; Cit,Met,QA, 0.798; Thr,AnthA,Kyn, 0.798; Val,Kyn,XA, 0.798; ABA,Trp,Kyn, 0.798; Arg,Val,Kyn, 0.796; Ser,Val,Kyn, 0.796; Ser,Trp,Kyn, 0.796; Asn,Trp,Kyn, 0.796; Thr,Leu,Kyn, 0.796; hKyn,AnthA,XA, 0.794; Also,Leu,NP, 0.794; Orn,Industry,QA, 0.794; Thr,Val,Kyn, 0.792; Met,Trp,Kyn, 0.792; hKyn,AnthA,NP, 0.792; Thr,Trp,Kyn, 0.792; Orn,Leu,Trp, 0.792; Asn,Val,Gender, 0.79; Tyr,Val,Kyn, 0.79; Orn,Lys,Trp, 0.79; His,Ile,Kyn, 0.79; Val,Met,Kyn, 0.788; Val,Kyn,QA, 0.788; ABA,AnthA,QA, 0.788; Kyn,XA,NP, 0.788; Tyr,Orn,Trp,788; Tyr,AnthA,QA, 0.786; Arg,Trp,Kyne, 0.786; Ile,AnthA,QA, 0.786; Orn,XA,NP, 0.786; Cit,Trp,hKyne, 0.786; Vale,Ile,Kyne, 0.784; Tyr, AnthA, Kyn, 0.784; Val,Kyn,NP, 0.783; Arg, Orn, Trp, 0.783; Thr,Cit,QA, 0.781; Cit,Arg,QA, 0.781; Met,Kyn,NP, 0.781; Val,Leu,Kyn, 0.779; Orn,QA,NP, 0,779; Cit,Lys,QA, 0.779; His,Cit,QA, 0.779; Val,AnthA,XA, 0.777; Val,Ile,AnthA, 0.777; Arg,AnthA,NP, 0.777; Val,Orn,hKyn, 0.775; AnthA,QA,NP, 0.775; Cit,QA,XA, 0.775; Thr,Arg,Kyn, 0.775; Ala,Val,AnthA, 0.775; AnthA,Kyn,NP, 0.773; Met,AnthA,QA, 0.773; Val, Met, AnthA, 0.773; Arg,Kyn,XA, 0.773; Arg,QA,XA, 0.773; Arg,Met,Kyne, 0.773; Thr,AnthA,QA, 0.771; Val, Orn, AnthA, 0.771; Val, Orn, Trp, 0.771; Arg, Val, AnthA, 0.769; Thr,hKyn,AnthA, 0.769; Cit,Val,AnthA, 0.769; Thr,Val,AnthA, 0.769; Arg, Trp, QA, 0.769; His,Orn,QA, 0.766; Arg,Kyn,NP, 0.764; ABA,Val,AnthA, 0.764; Ala,AnthA,QA, 0,764; Trp,AnthA,QA, 0.762; His,AnthA,QA, 0.76; Asn,Arg,Kyn, 0.76; Thr,Orn,QA, 0.758; Arg, AnthA, Kyn, 0.758; Arg,Orn,QA, 0.75; Thr,Cit,AnthA,

[0170] [118. Four-variable equation obtained from amino acids and amino acid-related metabolites after the start of treatment] Cit,Leu,hKyn,Kyn, 0.834; Similarly, ABA, Ile, Kyn, 0.834; Asn,ABA,Orn,QA, 0.832; ABA,Orn,Trp,Kyn, 0.83; ABA,Orn,Trp,QA, 0.828; ABA,Tyr,Orn,QA, 0.828; Ala, ABA, Orn, QA, 0.826; Gln,Cit,Trp,Kyn, 0.824; How,Tyr,Val,Type, 0.824; Ala,Orn,Trp,Kyn, 0.822; Orn,Lys,Trp,Kyn, 0.822; Ser,Orn,Trp,QA, 0.82; Also, Leu,HKyn,QA, 0.819; Val,Orn,AnthA,QA, 0.817; Tyr,AnthA,Kyn,XA, 0.817; His,Orn,Trp,hKyn, 0.817; Tyr,Leu,AnthA,Kyn, 0.817; Asn,OR,Leu,hKyn, 0.817; Tyr,Orn,Trp,QA, 0.815; Thr,Orn,Trp,Kyn, 0.815; Cit,Tyr,QA,NP, 0.815; Gln,ABA,Orn,QA, 0.815; His,Cit,Trp,QA, 0.815; Lys,Leu,AnthA,QA, 0.815; Orn,Leu,hKyn,XA, 0.815; Val,Lys,AnthA,Kyn, 0.813; Cit,ABA,Lys,QA, 0.813; Thr,Cit,Val,Kyn, 0.813; Also, ABA,Val,QA, 0.813; Asn,Orn,Trp,hKyn, 0.813; Arg,Iron,Trp,hKyn, 0.813; Thr,Orn,Trp,hKyn, 0.813; Cit,Lys,Leu,QA, 0.813; ABA,Leu,AnthA,Kyn, 0.813; Met,Orn,Kyn,NP, 0.813; Orn,Leu,QA,XA, 0.813; Val,hKyn,AnthA,Kyn, 0.811; Orn,Trp,hKyn,AnthA, 0.811; Ala,Cit,Trp,Kyn, 0.811; Ala,Orn,Trp,hKyn, 0.811; Asn,Val,Orn,Why, 0.811; Orn, Trp, AnthA, QA, 0.809; Cit,Tyr,AnthA,QA, 0.809; Val, Orn, hKyn, AnthA, 0.809; Leu, hKyn, AnthA, NP, 0.809; His,Cit,Leu,QA, 0.809; Val,Orn,QA,XA, 0.809; Cit,Tyr,Ile,QA, 0.809; Thr,ABA,Orn,QA, 0.809; Val, AnthA, Kyn, NP, 0.807; Val, Orn, AnthA, NP, 0.807; Cit,Val,Trp,QA, 0.807; Val,Orn,Light,QA, 0.807; Cit,Leu,AnthA,NP, 0.807; ABA,Val,Orn,QA, 0.805; Orn, hKyn, AnthA, NP, 0.805; Cit,ABA,Ile,QA, 0.803; Ser, Trp, AnthA, Kyn, 0.803; Val,Orn,Ile,QA, 0.803; ABA, Leu, hKyn, AnthA, 0.803; Val, AnthA, Kyn, XA, 0.802; Val, Met, AnthA, Kyn, 0.802; Cit , Val , hKyn , AnthA , 0.802 ; Arg, Leu, AnthA, Kyn, 0.8; Gln, Val, AnthA, Kyn, 0.8; Val, Ile, AnthA, Kyn, 0.8; Meth, Orn, Trp, hKyne, 0.8; Ser,Cit,Val,QA, 0.8; Trp,AnthA,Kyn,XA, 0.8; Tyr, Orn, QA, XA, 0.8; Cit,QA,XA,NP, 0.8; Asn, Arg, Leu, Kyn, 0.798; Val,AnthA,QA,XA, 0.798; Gln,Cit,Tyr,QA, 0.798; Arg, Val, AnthA, Kyn, 0.796; Arg,Ile,AnthA,Kyn, 0.796; ABA,Val,hKyn,AnthA, 0.796; Val,Trp,AnthA,QA, 0.796; Asn,Cit,Val,hKyn, 0.796; Ser,Cit,Trp,QA, 0.796; Taurus,Val,Orn,hKyn, 0.796; Arg, Val, hKyn, AnthA,794; Arg,Val,Kyn,XA, 0.794; Arg,Ile,AnthA,QA, 0.792; Arg,ABA,Leu,Kyn, 0.79; Arg,Val,Trp,Kyn, 0.79; Gln,Arg,Val,Kyn, 0.79; Asn,Leu,hKyn,AnthA, 0.79; Val,Ile,hKyn,AnthA, 0.786; Arg,Tyr,AnthA,Kyn, 0.786; Thr,Cit,Kyn,QA, 0.786; Ser,Val,Orn,hKyn, 0.786; Arg,Val,Lys,Kyn, 0.784; Thr,Tyr,AnthA,QA, 0.784; Arg,Val,AnthA,QA, 0.783; His,Val,Kyn,NP, 0.783; Thr,Arg,Leu,Kyn, 0.781; Gln,Arg,Leu,Kyn, 0.781; Thr,Arg,AnthA,QA, 0.775; Tyr,Trp,AnthA,QA, 0.769.

[0171] [119.This song is in the same page] Cit,Lys,Leu,hKyn,AnthA, 0.845; Similarly, ABA, Orn, Ile, QA, 0.834; Cit,Tyr,Lys,Leu,QA, 0.834; Ser,Orn,Lys,Trp,Kyn, 0.834; Ala,Val,Lys,AnthA,Kyn, 0.832; Thr,Cit,ABA,Kyn,QA, 0.832; Ser,Tyr,Iron,Trp,Kyn, 0.832; His,Cit,Val,Kyn,NP, 0.83; For example, ABA,Kyn,QA,NP, 0.83; Gln,Cit,Trp,hKyn,Cyn, 0.83; His,Cit,Val,Trp,Kyn, 0.828; Ser,Met,Orn,Trp,Kyn, 0.828; Val,Lys,hKyn,AnthA,NP, 0.826; Ala,Cit,ABA,Trp,Kyn, 0.826; Asn,Cit,Trp,Kyn,XA, 0.826; Also,Arg,Leu,Kyn,NP, 0.824; Gln,Orn,Trp,Kyn,QA, 0.824; Asn,Orn,Trp,Kyn,QA, 0.824; Cit,Tyr,Ile,Trp,Kyn, 0.824; Val,Met,Lys,AnthA,Kyn, 0.822; Asn,Gln,Cit,Trp,Kyn, 0.822; Cit,ABA,Val,Met,Kyn, 0.822; Val,Orn,Ile,Trp,Kyn, 0.822; Ala,Cit,Leu,Trp,Kyn, 0.82; Cit,ABA,Val,Trp,Kyn, 0.82; Ser,Met,Orn,Trp,QA, 0.82; Thr,Cit,Leu,Kyn,QA, 0.82; Tyr,Orn,Trp,hKyn,Kyn, 0.82; Leu,AnthA,Kyn,QA,NP, 0.82; Val,Orn,Trp,AnthA,QA, 0.819; Cit,Tyr,Val,AnthA,QA, 0.819; Gln,Cit,Val,AnthA,Kyn, 0.819; Also,Val,Ile,Type,NP, 0.819; Thr,Cit,ABA,Trp,Kyn, 0.819; His,Orn,Ile,Trp,QA, 0.819; Cit,Lys,Leu,Trp,Kyn,0.819; Asn,Cit,Val,Orn,Kyn, 0.819; Leu, AnthA, Kyn, XA, NP, 0.819; Orn,Leu,AnthA,QA,XA, 0.819; Orn,Lys,Trp,hKyn,AnthA, 0.817; Val, Orn, hKyn, AnthA, NP, 0.817; Cit, Leu, Trp, AnthA, Kyn, 0.817; Cit,Leu,hKyn,AnthA,QA, 0.817; Ser,Val,Lys,AnthA,Kyn, 0.817; Ser,Orn,Trp,QA,XA, 0.817; His,Orn,Trp,QA,XA, 0.817; Wing,Tyr,Orn,Trp,QA, 0.817; Ala,Orn,Ile,Trp,QA, 0.817; Meth, Orn, Trp, QA, NP, 0.817; His,Cit,Val,Kyn,QA, 0.817; Arg,Lys,Trp,AnthA,Kyn, 0.817; Gln,Val,Lys,AnthA,Kyn, 0.815; Tyr,Val,hKyn,AnthA,Kyn, 0.815; Orn,Ile,Trp,QA,NP, 0.815; Cit, Orn, Light, Trp, hKyn, 0.815; Ala, Orn, Trp, AnthA, QA, 0.813; Cit,Tyr,Val,Trp,Kyn, 0.813; Ser,Val,Ile,AnthA,Kyn, 0.813; Gln,Tyr,Orn,Trp,QA, 0.813; Asn,Cit,Trp,Kyn,NP, 0.813; Asn,Thr,Cit,Trp,Kyn, 0.813; His,Ala,Val,AnthA,Kyn, 0.811; Val, Orn, Leu, Kyn, NP, 0.811; Thr,Arg,Orn,Trp,QA, 0.811; Thr,Cit,Trp,Kyn,NP, 0.811; Cit, Val, Met, AnthA, Kyn, 0.809; Arg,Val,Lys,hKyn,AnthA, 0.809; Thr,Cit,Leu,AnthA,QA, 0.809; Ala,ABA,Val,AnthA,Kyn, 0.809; Arg,Val,Lys,AnthA,Kyn, 0.807; Arg, Val, AnthA, Kyn, NP,807; Arg,Orn,Trp,AnthA,QA, 0.807; Gln,Val,AnthA,Kyn,NP, 0.807; Val,Orn,Leu,Trp,QA, 0.807; Arg, ABA, Val, Orn, QA, 0.807; Thr,Cit,Ile,AnthA,Kyn, 0.805; His,Arg,Val,AnthA,Kyn, 0.803; Gln,Arg,Val,AnthA,Kyn, 0.803; Arg, Orn, Leu, hKyn, AnthA, 0.803; Thr,Cit,Trp,Kyn,QA, 0.803; Arg,Val,Lys,Kyn,NP, 0.803; Arg,Val,Lys,AnthA,QA, 0.802; Ser,Arg,Val,AnthA,Kyn, 0.802; Thr,Cit,Ile,Trp,Kyn, 0.802; His,Cit,Arg,Val,Kyn, 0.802; Arg,Lys,Ile,AnthA,Kyn, 0.802; Arg,Val,AnthA,Kyn,QA, 0.8; Arg,Tyr,Lys,AnthA,QA, 0.8; Arg,ABA,Val,Orn,Kyn, 0.8; Arg,ABA,Val,AnthA,Kyn, 0.798; Thr,Arg,Val,AnthA,Kyn, 0.798; Arg,Val,Leu,AnthA,Kyn, 0.798; Asn,Val,Ile,AnthA,Kyn, 0.798; Gln,Val,Ile,AnthA,Kyn, 0.798; Arg,Val,Ile,AnthA,Kyn, 0.796; Arg,Val,AnthA,Kyn,XA, 0.796; Ala,Arg,Val,Lys,Kyn, 0.796; Arg,Val,Orn,Lys,Kyn, 0.796; Thr,Cit,hKyn,AnthA,QA, 0.792; Arg,Val,Lys,AnthA,XA, 0.784;.

[0172] [120.This song is in the same page] Cit,ABA,Tyr,Lys,AnthA,QA, 0.858; Cit,Tyr,Lys,Trp,AnthA,QA, 0.851; Cit,Tyr,Lys,AnthA,QA,XA, 0.849; Ser,Cit,Tyr,Lys,AnthA,QA, 0.847; Cit,Tyr,Lys,AnthA,Kyn,QA, 0.847; Cit,Tyr,Lys,AnthA,QA,NP, 0.845; Gln,Ala,Cit,Lys,Trp,Kyn, 0.845; Met,Orn,Leu,AnthA,Kyn,NP, 0.843; Ser,Cit,ABA,Tyr,Lys,QA, 0.843; Cit,Tyr,Lys,Ile,AnthA,QA, 0.841; Cit,Tyr,Orn,Lys,AnthA,QA, 0.841; Cit,ABA,Lys,Ile,Trp,Kyn, 0.841; Cit, ABA, Met, Lys, Kyn, QA, 0.836; Cit,ABA,Tyr,Kyn,XA,NP, 0.836; Similarly, ABA, Ile, Leu, Kyn, QA, 0.834; Gln, Cit, ABA, AnthA, Kyn, QA, 0.834; Gln,Cit,Met,Trp,Kyn,NP, 0.834; Tyr,Val,Orn,Lys,AnthA,QA, 0.832; Gln,His,Cit,Val,Trp,Kyn, 0.832; Gln,Cit,ABA,Val,Kyn,XA, 0.832; Ala,Orn,Lys,Trp,AnthA,Kyn, 0.83; Cit,Tyr,Orn,Lys,Trp,QA, 0.83; Ala,Cit,Leu,AnthA,Kyn,QA, 0.83; Asn,Gln,Orn,Lys,Trp,QA, 0.828; His,Cit,Trp,AnthA,Kyn,NP, 0.828; Cit,Arg,ABA,Tyr,Lys,QA, 0.828; His,Orn,Lys,Leu,QA,NP, 0.828; Gln,Cit,ABA,Tyr,AnthA,QA, 0.826; His,Orn,Trp,AnthA,Kyn,QA, 0.826; Thr,Val,Orn,Ile,Kyn,NP, 0.826; Thr,Orn,Leu,hKyn,AnthA,Kyn,0.826; His,Cit,ABA,Orn,QA,NP, 0.826; Cit,Tyr,Orn,Trp,Kyn,XA, 0.826; Ser,Tyr,Trp,AnthA,Kyn,XA, 0.826; Arg, ABA, Orn, Lys, QA, XA, 0.824; Arg,Orn,Trp,hKyn,Kyn,QA, 0.824; Ser,Asn,Thr,Orn,Trp,QA, 0.824; Ser,Asn,Tyr,Orn,Trp,QA, 0.824; Ala,Cit,Val,Ile,Kyn,XA, 0.824; Cit,ABA,Tyr,Orn,AnthA,QA, 0.822; ABA, Orn, Trp, HKyn, AnthA, QA, 0.822; Orn,Leu,Trp,Kyn,QA,NP, 0.822; Cit, ABA, Val, Lys, AnthA, QA, 0.82; Similarly, ABA, Tyr, Ile, AnthA, QA, 0.82; Cit,Tyr,Met,AnthA,QA,NP, 0.82; Cit,Tyr,Met,AnthA,Kyn,QA, 0.82; Cit,Ile,Trp,AnthA,Kyn,NP, 0.82; Ala,Val,hKyn,AnthA,Kyn,QA, 0.82; Cit,Tyr,Val,Kyn,QA,XA, 0.82; Thr,Orn,Trp,hKyn,Kyn,NP, 0.82; Val,Orn,Leu,hKyn,AnthA,NP, 0.819; Val,Orn,Leu,hKyn,AnthA,QA, 0.819; Cit,Tyr,Met,Trp,AnthA,QA, 0.817; Cit,ABA,Tyr,HKyn,AnthA,QA, 0.817; Gln,Cit,Tyr,Trp,AnthA,QA, 0.817; Ala,Cit,Met,Trp,Kyn,NP, 0.817; Also, ABA, Leu, AnthA, QA, XA, 0.815; Thr,Cit,Leu,Trp,Kyn,NP, 0.815; His,Val,Ile,hKyn,AnthA,Kyn, 0.815; Gln,ABA,Val,Lys,AnthA,Kyn, 0.815; Cit,Val,Leu,Trp,hKyn,Kyn, 0.815; Arg,ABA,Val,Lys,AnthA,Kyn,0.813; Asn,Cit,Arg,Leu,AnthA,Kyn, 0.813; Asn,Cit,Leu,hKyn,AnthA,NP, 0.813; Ser,Thr,Val,Trp,AnthA,Kyn, 0.813; Ala,Cit,Orn,Trp,QA,NP, 0.813; Arg,Tyr,Lys,Leu,AnthA,QA, 0.811; Asn,Cit,Val,Lys,Ile,hKyn, 0.811; Cit, ABA,Val,Trp,AnthA,QA, 0.811; Gln,Val,Trp,AnthA,Kyn,NP, 0.811; Thr,ABA,Val,Orn,HKyn,AnthA, 0.811; Ser,Asn,Thr,Val,AnthA,Kyn, 0.811; Asn,His,Cit,Leu,QA,XA, 0.811; Similarly, Ile,Leu,Trp,HKyn,AnthA, 0.811; Cit,Ile,Leu,Trp,hKyn,Kyn, 0.809; Ser,Cit,Leu,Trp,hKyn,Kyn, 0.809; Cit,Tyr,Orn,Trp,HKyn,AnthA, 0.809; Ala,Val,Lys,Leu,AnthA,QA, 0.809; Arg,Lys,Leu,Trp,AnthA,Kyn, 0.807; Ser,Arg,Leu,AnthA,Kyn,NP, 0.807; His,Ala,Arg,Leu,AnthA,Kyn, 0.807; Ser,Thr,Orn,Trp,HKyn,AnthA, 0.807; Arg,ABA,Val,Lys,AnthA,NP, 0.805; Arg,Tyr,AnthA,Kyn,XA,NP, 0.805; Gln,Ala,ABA,Val,AnthA,Kyn, 0.805; Cit,Met,Leu,Trp,hKyn,Kyn, 0.805; Asn,Arg,ABA,Val,Lys,Kyn, 0.803; Thr,Cit,Ile,AnthA,Kyn,QA, 0.803; Asn,Orn,Trp,hKyn,AnthA,NP, 0.803; Arg,Orn,Ile,Leu,AnthA,QA, 0.802; Thr,Tyr,Val,AnthA,Kyn,NP, 0.802; Arg,Tyr,Met,Leu,HKyn,AnthA,0.8; Ser,Arg,Met,Leu,AnthA,Kyn, 0.798; Arg,ABA,Val,Ile,AnthA,Kyn, 0.796; Asn,Arg,Val,Lys,Kyn,XA, 0.794; Ser,Gln,Val,Ile,AnthA,Kyn, 0.794; Thr,Val,Ile,AnthA,Kyn,QA, 0.794; Asn,Ala,Val,Leu,AnthA,Kyn, 0.792; Thr,Arg,ABA,Lys,AnthA,QA, 0.786; Asn,Gln,Arg,Val,Lys,hKyn, 0.779.

[0173] [201. Two-variable equation obtained from amino acids before the start of treatment] Ala,Arg, 0.825; Asn,Ala, 0.819; His,Ala, 0.819; Ala,Cit, 0.817; Ala,Orn, 0.817; Ala,Ile, 0.817; Ala,Pro, 0.817; Gln,Ala, 0.817; Ala,Val, 0.817; Ala,Lys, 0.817; Glu,Ala, 0.817; Ala,Met, 0.816; Ala,Trp, 0.816; Ala,Phe, 0.816; Ala,Leu, 0.816; Gly,Ala, 0.814; Ala,Tyr, 0.814; Thr,Ala, 0.813; Ala,ABA, 0.813; Ser,Ala, 0.805; Pro,Lys, 0.766; Orn,Trp, 0.751; His,Pro, 0.746; Arg,Pro, 0.745; Pro,Trp, 0.738; Arg,Trp, 0.738; Lys,Trp, 0.734; Glu,Lys, 0.731; Arg,Orn, 0.729; His,Trp, 0.726; Gly,Lys, 0.726; Thr,Pro, 0.726; His,Arg, 0.726; Orn,Lys, 0.723; Asn,Pro, 0.723; Ser,Lys, 0.723; Gln,Lys, 0.721; His,Lys, 0.721; Pro,Val, 0.721; Arg,Tyr, 0.72; Val,Lys, 0.72; His,Tyr, 0.72; Arg,Val, 0.718; ABA,Lys, 0.718; Asn,Trp, 0.717; Ser,Arg, 0.717; Thr,Lys, 0.715; Thr,Trp, 0.714; Glu,Arg, 0.714; Pro,Tyr, 0.712; Pro,Met, 0.712; Glu,Asn, 0.712; Glu,Trp, 0.711; Cit,Lys, 0.711; Lys,Phe, 0.711; Arg,Ile, 0.711; Pro,ABA, 0.711; Gln,Pro, 0.711; Tyr,Lys, 0.709; Gly,Trp, 0.709; Val,Trp, 0.709; Arg,Lys, 0.707; Tyr,Trp, 0.707; Ile,Trp, 0.707; Ser,Trp, 0.707; Lys,Leu, 0.707; Lys,Ile, 0.707; Asn,Lys, 0.706; Met,Trp, 0.704; Gln,Trp, 0.703; Met,Lys, 0.703; Arg,Leu, Gly,Arg, 0.701; Cit,Trp, 0.698; Cit,Arg, 0.698; Gly,Pro, 0.698; Arg,Met, 0.698; Arg,Phe, 0.698; Ser, Pro, Val,Leu, 0.698; Cit,Tyr, 0.698; ABA,Trp, 0.697; Thr,Arg, 0.697; Pro,Leu, 0.695; Pro,Ile, 0.693; Leu,Trp, 0.692; Glu,Pro, 0.692; Pro,Phe, 0.69; Gly,Tyr, 0.678; Asn,Tyr, 0.675; Gln,Tyr, 0.675; Tyr,Orn, 0.675; Asn,Val, 0.666; Tyr,Phe, 0.638.

[0174] [202. Three-variable equation obtained from amino acids before the start of treatment] Ala,Arg,Met, 0.833; Asn,Ala,Arg, 0.828; His,Ala,Arg, 0.828; Ala,Arg,Leu, 0.828; Ala,Arg,Val, 0.827; Glu,Ala,Arg, 0.827; Ala,Arg,Phe, 0.825; Ala,Arg,Lys, 0.825; Ala,Arg,Pro, 0.825; Ala,Cit,Met, 0.824; Asn,Ala,Cit, 0.824; Ala,Arg,Trp, 0.824; Ala,Arg,Ile, 0.824; Gly,Ala,Arg, 0.824; Glu,Asn,Ala,Phe, 0.82; Ala,Met,Leu, 0.82; Ala,Cit,Arg, 0.82; His, Ala, Pro, 0.82; Gln, His, Ala, 0.82; Ala,ABA,Met, 0.819; His, Ala, Met, 0.819; Asn, Ala, Pro, 0.819; Ala, Orn, Trp, 0.819; Asn, Gln, Ala, 0.819; Asn, Ala, Leu, 0.819; Ala,Arg,ABA, 0.819; Gly, Thr, Ala, 0.819; Thr,Ala,Phe, 0.819; His, Ala, Val, 0.819; Ala,Met,Trp, 0.817; Ala,Cit,Trp, 0.817; Gly,Ala,Cyt, 0.817; Ala,Cyt,Lys, 0.817; Glu,Ala,Cyt, 0.817; Ala,Leu,Trp, 0.817; Ala,Phe,Trp, 0.817; His,Ala,Orn, 0.817; His,Ala,Leu, 0.817; Ala,Pro,Trp, 0.817; Ala,Ile,Trp, 0.817; Glu,Ala,Orn, 0.817; Gln,Ala,Orn, 0.817; Asn,Thr,Ala, 0.816; Glu,Ala,Met, 0.816; Gly,His,Ala, 0.816; Gln,Thr,Ala, 0.816; Thr,Ala,Arg, 0.814; Asn,Ala,ABA, 0.814; His,Ala,Cit, 0.814; Ala,Val,Met, 0.814; Ala,Pro,Met, 0.814; Ala,Cit,Pro, 0.814; Thr,Ala,Lys, 0.814; Ala,Tyr,Phe, 0.814; Ala,Orn,Phe, 0.814; Gly, Gln, Ala, 0.814; Ala, Val, Orn, 0.814; Ala, Val, Ile, 0.814; Asn, Ala, Trp, 0.813; Ala,ABA,Trp, 0.813; Thr,Ala,Orn, 0.813; Glu,Ala,ABA, 0.813; Gly,Ala,Orn, 0.813; Ala, Tyr, Orn, 0.813; Ala,Pro,Orn, 0.813; Ala, Tyr, Leo, 0.813; Ala, Pro, Phe, 0.813; Gln, Ala, Phe, 0.813; Glu,Ala,Phe, 0.813; Ala, Cit, Orn, 0.811; Asn, His, Ala, 0.811; Asn, Ala, Ile, 0.811; Ser,Ala,Pro, 0.811; Ala,Cit,Ile, 0.811; His, Ala, ABA, 0.811; His, Ala, Lys, 0.811; Gly,Ala,ABA, 0.811; Ala, Lys, Trp, 0.811; Ala,ABA,Tyr, 0.811; Ala,ABA,Ile, 0.811; Gly,Ala,Tyr, 0.811; Ser,Ala,Lys, 0.81; Ala,ABA,Leu, 0.81; Thr,Ala,Val, 0.81; Gln,Ala,ABA, 0.81; His,Thr,Ala, 0.808; Ala,ABA,Phe, 0.808; Ala,Ile,Phe, 0.808; Ala,Tyr,Met, 0.807; Thr,Ala,Trp, 0.807; Ser,Ala,Phe, 0.805; Ser,His,Ala, 0.805; Ser,Ala,Leu, 0.805; Ala,Cit,ABA, 0.805; Ser,Ala,Ile, 0.805; Ser,Ala,Arg, 0.803; Ser,Ala,Trp, 0.803; Ser,Ala,Met, 0.803; Glu,Ser,Ala, 0.802.

[0175] [203. Four-variable equation obtained from amino acids before the start of treatment] Ala,Arg,Met,Leu, 0.834; His, Ala, Arg, Met, 0.833; Gly, Ala, Arg, Met, 0.831; Ala,Arg,Met,Ile, 0.83; Ala,Arg,Met,Lys, 0.83; His, Ala, Arg, Ile, 0.83; Gln, Ala, Arg, Met, 0.828; Ala, Arg, Orn, Lys, 0.828; Asn, Gly, Thr, Ala, 0.828; Ala,Arg,Val,Met, 0.827; Asn, Ala, Arg, Tyr, 0.827; Thr, Ala, Arg, Orn, 0.825; Thr, Ala, Arg, Met, 0.825; Ala, Cyt, Arg, Met, 0.825; Asn, Ala, Cyt, Phe, 0.825; Ala,Arg,Tyr,Orn, 0.825; Gly,Ala,Arg,Orn, 0.825; Glu,His,Ala,Arg, 0.825; Glu,Ala,Cit,Met, 0.824; Asn,Ala,Cit,Pro, 0.824; Asn,Ala,Cit,Leu, 0.824; Ala,Arg,Orn,Ile, 0.824; Ala,Arg,Tyr,Met, 0.822; Ala,Arg,ABA,Met, 0.822; Ala,Cit,Met,Trp, 0.822; Ala,Arg,Met,Phe, 0.822; Thr,Ala,Cit,Met, 0.822; Ala,Cit,Pro,Met, 0.822; Asn,Gly,Ala,Val, 0.822; Asn,Gly,Ala,Phe, 0.822; Asn, Gly, His, Ala, 0.82; Asn, Ala, ABA, Leu, 0.819; His, Ala, ABA, Met, 0.819; Asn, Ala, Orn, Lys, 0.819; Asn, Ala, Val, Lys, 0.819; His, Ala, Met, Orn, 0.819; Thr,Ala,Arg,Ile, 0.817; Ala,Cit,Orn,Trp, 0.817; Glu,Thr,Ala,Arg, 0.817; Asn, Ala, Met, Leu, 0.817; Gln, His, Ala, Met, 0.817; Gly, Ala, Met, Ile, 0.816; Asn,Ala,ABA,Trp, 0.816; Ser,Ala,Orn,Trp, 0.816; His,Ala,Cit,Trp, 0.816; Glu,Asn,Ala,Met, 0.816; Asn,Ala,Tyr,Orn, 0.816; Ala,Val,Met,Orn, 0.816; Asn,Gln,Thr,Ala, 0.816; Ala,Cit,Met,Ile, 0.814; His,Ala,Met,Trp, 0.814; Ala,Met,Lys,Ile, 0.814; Thr,Ala,Cit,Pro, 0.814; Asn,His,Ala,Trp, 0.813; Ala,Cit,Val,Orn, 0.813; His,Ala,Cit,Ile, 0.813; Asn,Ala,Val,Leu, 0.813; Asn,Ala,Tyr,Ile, 0.813; His,Ala,ABA,Trp, 0.813; Gly,Thr,Ala,Leu, 0.813; Glu,Ala,Pro,Met, 0.813; Ser,Ala,Arg,Met, 0.811; Thr,Ala,Arg,Leu, 0.811; Thr,Ala,Arg,Pro, 0.811; Gln,Ala,Arg,Lys, 0.811; Ser,His,Ala,Arg, 0.81; Asn,Thr,Ala,Trp, 0.81; Ser,Ala,Tyr,Met, 0.81; Ala,Met,Ile,Phe, 0.81; Ser,Ala,Lys,Leu, 0.81; His,Ala,Lys,Trp, 0.81; Ala,Cit,ABA,Val, 0.81; Glu,Thr,Ala,ABA, 0.81; Thr,Ala,ABA,Val, 0.81; Ser,His,Ala,Cit, 0.808; Glu,Ala,Cit,Orn, 0.808; Ala,Tyr,Ile,Leu, 0.808; His,Ala,Pro,Met, 0.807; Asn,His,Ala,Phe, 0.807; Asn,Ala,Pro,Ile, 0.807; Ser,His,Ala,Leu, 0.807; Ser,Ala,Arg,Phe, 0.805; Ala,Pro,Tyr,Met, 0.805; Ser,Asn,Ala,Tyr, 0.805; Glu, Gln, Ala, Cit, 0.805; Ala, Cit, ABA, Lys, 0.805; Ser, His, Ala, Trp, 0.803; Ser, Ala, Cit, Pro, 0.803; Ser, Ala, Pro, Trp, 0.803; Ser, Asn, His, Ala, 0.803; Ser, Ala, Lys, Phe, 0.803; Ser, Ala, ABA, Orn, 0.803; Gln, Ala, Cit, Leu, 0.803; Ser, Ala, Val, Ile, 0.803; Ser, Gln, Ala, Arg, 0.802; His, Thr, Ala, Val, 0.802; Ser, Ala, Arg, Trp, 0.8; Ser, Ala, Ile, Phe, 0.8; Ser, Asn, Ala, Ile, 0.8; Ser, Ala, Cit, Leu, 0.797.

[0176] [5-variable formula obtained from amino acids before treatment start] Glu, Asn, Ala, Arg, Orn, 0.841; Glu, Ala, Arg, Met, Orn, 0.836; Glu, Ala, Arg, Met, Leu, 0.833; Asn, Gly, Thr, Ala, Arg, 0.831; Ala,Arg,Tyr,Met,Ile, 0.828; Thr, Ala, Arg, Met, Orn, 0.828; Asn, Gly, Ala, Met, Trp, 0.828; His, Ala, Arg, Pro, Phe, 0.828; Ala, Arg, Orn, Leu, Phe, 0.828; Asn, Gly, Ala, Pro, Met, 0.827; Ala,Arg,Val,Met,Ile, 0.825; Ala,Arg,ABA,Met,Orn, 0.825; His, Ala, Arg, Met, Orn, 0.825; Asn,Ala,Cit,ABA,Ile, 0.825; Ser,Asn,Ala,Cit,Ile, 0.825; His,Ala,Cit,Arg,Tyr, 0.825; His,Ala,Arg,Met,Leu, 0.824; Asn,His,Ala,Cit,Phe, 0.824; Asn,Ala,Cit,Pro,ABA, 0.824; Ala,Arg,Tyr,Met,Orn, 0.822; Ser,Thr,Ala,Arg,Orn, 0.822; His,Thr,Ala,Arg,Orn, 0.822; Glu,Ala,Arg,ABA,Met, 0.822; Asn,His,Ala,Cit,Trp, 0.822; Ala,Cit,Met,Lys,Leu, 0.822; Asn, Ala, Pro, Orn, Trp, 0.822; Asn, Gly, Thr, Ala, Lys, 0.822; Asn, Gly, Ala, Pro, Lys, 0.822; Asn, Ala, Cyt, ABA, Orn, 0.82; Thr, Ala, Arg, Ile, Phe, 0.82; Gly, Ala, Met, Orn, Trp, 0.82; Asn, Ala, Arg, Tyr, Ile, 0.82; Asn, Ala, Tyr, Lys, Phe, 0.82; Ser, Asn, Gly, Ala, Arg, 0.819; Ala,Cit,Met,Leu,Trp, 0.819; Asn, Thr, Ala, Cyt, Tyr, 0.819; Asn,Gly,Ala,Tyr,Met, 0.819; Gln,His,Ala,Arg,Trp, 0.819; Ala,Cit,Orn,Ile,Trp, 0.817; Glu,Gln,Ala,Cit,Met, 0.817; Ala,ABA,Val,Ile,Leu, 0.817; His,Ala,Cit,Tyr,Trp, 0.817; Glu,Ser,Ala,Arg,Met, 0.816; Asn,His,Ala,Cit,Met, 0.816; Asn,Gln,Ala,Met,Trp, 0.816; Glu,Asn,Ala,Val,Trp, 0.816; Thr,Ala,Arg,Lys,Phe, 0.816; Ser,Asn,Ala,Lys,Leu, 0.816; Ser,Ala,Arg,Orn,Lys, 0.814; Ser,Asn,Gly,Ala,Ile, 0.814; Thr,Ala,Arg,Val,Trp, 0.814; Asn,Ala,Met,Lys,Trp, 0.814; Gly,Ala,Cit,Orn,Phe, 0.814; Gly,Ala,ABA,Met,Orn, 0.814; His,Ala,Orn,Lys,Trp, 0.814; Ser,Ala,Arg,Met,Orn, 0.813; Ser,Gly,Ala,Arg,Met, 0.813; Asn,Thr,Ala,Lys,Trp, 0.813; Asn,Ala,ABA,Met,Leu, 0.813; Asn,His,Ala,Val,Phe, 0.813; Ser,Asn,His,Ala,Trp, 0.811; Ala,ABA,Met,Leu,Trp, 0.811; Thr,Ala,Arg,Pro,Lys, 0.811; Asn,Ala,ABA,Val,Ile, 0.811; Glu,Ala,Cit,Orn,Lys, 0.811; Ala,ABA,Ile,Leu,Phe, 0.811; Gln,His,Ala,Orn,Trp, 0.811; Gly,Ala,Tyr,Met,Ile, 0.81; Glu,Ser,Gly,Ala,Cit, 0.81; Ala,Tyr,Ile,Leu,Trp, 0.81; Glu,Ser,Ala,Orn,Trp, 0.81; His, Ala, Pro, Met, Lys, 0.81; Ser, Asn, Gly, Ala, Phe, 0.808; Asn, Thr, Ala, Pro, Trp, 0.808; Ser,Gly,Ala,Val,Lys, 0.808; Ser,Thr,Ala,Cyt,Val, 0.808; Ser,Ala,Tyr,Met,Orn, 0.808; Gln, Thr, Ala, Met, Ile, 0.808; Ser, Ala, Arg, Ile, Leu, 0.807; Asn, Ala, Val, Ile, Trp, 0.807; Ala, ABA, Tyr, Met, Phe, 0.807; Ser, Ala, Pro, Tyr, Met, 0.807; Asn, Ala, Pro, Met, Ile, 0.807; Ser, Ala, Met, Orn, Trp, 0.805; His, Thr, Ala, Leu, Trp, 0.805; Ser, Gly, Thr, Ala, Leu, 0.805; Ser, Ala, ABA, Met, Orn, 0.805; Asn, His, Ala, Pro, Lys, 0.805; Ser, Ala, Tyr, Leu, Phe, 0.805; Ser, Ala, Cyt, Pro, Phe, 0.803; Glu, Ser, Ala, Met, Trp, 0.802; Glu, Ser, Gln, Ala, Arg, 0.802; His, Thr, Ala, Orn, Trp, 0.802; Thr, Ala, Pro, ABA, Phe, 0.802; Ser, Asn, Ala, Pro, Phe, 0.802; Ser, Gln, His, Ala, Trp, 0.8; Ser, Ala, Met, Orn, Ile, 0.8; Thr, Ala, Ile, Leu, Trp, 0.799; Ser, Asn, His, Ala, Pro, 0.799; Ser, Asn, Ala, ABA, Phe, 0.794.

[0177]

[205] Asn,Ala,Arg,Orn,Ile,Trp, 0.837; Ala,Arg,Met,Orn,Ile,Trp, 0.836; Glu,Ala,Arg,Met,Orn,Ile, 0.834; Gly,His,Ala,Arg,ABA,Met, 0.834; Asn,Gly,Ala,Arg,Met,Trp, 0.834; Asn,Ala,Arg,ABA,Tyr,Met, 0.833; Glu,Ala,Arg,Val,Met,Orn, 0.833; Gly,Ala,Arg,Tyr,Val,Met, 0.831; Thr,Ala,Arg,ABA,Met,Ile, 0.83; Asn,Ala,Cit,Arg,ABA,Orn, 0.83; Asn,His,Thr,Ala,Arg,Leu, 0.828; Ala,Arg,Pro,ABA,Met,Ile, 0.827; Ser,Asn,Gly,Ala,Cit,Trp, 0.827; Ser,Asn,Ala,Arg,Pro,Orn, 0.827; Glu,Thr,Ala,Arg,ABA,Orn, 0.827; Asn,Ala,Cit,Met,Lys,Trp, 0.827; Asn,Thr,Ala,Arg,Met,Leu, 0.827; Asn,Gln,Thr,Ala,Arg,ABA, 0.827; Asn,Gln,Thr,Ala,Arg,Ile, 0.827; Ser,Asn,Ala,Cit,ABA,Trp, 0.827; His,Ala,Arg,Val,Met,Ile, 0.825; His,Ala,Arg,Met,Ile,Phe, 0.825; Glu,Ala,Arg,Tyr,Met,Trp, 0.825; Asn,Gly,Ala,ABA,Tyr,Trp, 0.825; Gly,Gln,His,Ala,Met,Trp, 0.825; Ser,Asn,Gly,Ala,ABA,Trp, 0.824; His,Ala,Cit,Arg,Met,Phe, 0.824; Asn,Gly,Ala,Pro,ABA,Trp, 0.824; Asn,His,Thr,Ala,Cit,Met, 0.824; Gly,Ala,Cit,ABA,Tyr,Met, 0.822; Ser,Asn,Gly,Ala,Cit,ABA, 0.822; Thr, Ala, Arg, Pro, Orn, Phe, 0.822; Asn, His, Ala, Cyt, Arg, Phe, 0.822; Thr,Ala,Arg,Met,Ile,Leu, 0.82; His, Ala, Cyt, Arg, Met, Ile, 0.82; Ala,Cyt,ABA,Tyr,Met,Leu, 0.82; Gln, Thr, Ala, Arg, Tyr, Met, 0.82; Ser, His, Ala, Cyt, Met, Ile, 0.82; Gly, Ala, Cyt, ABA, Val, Met, 0.82; Gln, Thr, Ala, Arg, Ile, Phe, 0.82; His, Ala, Cyt, Arg, Tyr, Met, 0.819; Glu, His, Thr, Ala, Arg, Ile, 0.819; Thr, Ala, Arg, Pro, Met, Phe, 0.819; Glu, Gly, Ala, Tyr, Met, Trp, 0.819; Glu, Ala, Cyt, Tyr, Met, Leu, 0.817; Glu,Thr,Ala,Arg,Tyr,Met, 0.817; Ser, Thr, Ala, Arg, Pro, Met, 0.817; Glu,Thr,Ala,Cyt,Met,Trp, 0.817; Ser, Ala, Cyt, ABA, Tyr, Met, 0.816; Ala,Cit,Pro,Met,Orn,Trp, 0.816; His, Ala, Cyt, Orn, Ile, Trp, 0.816; Ser, Asn, His, Ala, Arg, Trp, 0.816; His, Ala, Cyt, Tyr, Orn, Lys, 0.816; Gly,His,Thr,Ala,ABA,Trp, 0.816; Ala,Cit,Tyr,Met,Ile,Leu, 0.814; Ser,His,Ala,Arg,ABA,Met, 0.814; Ser,Ala,Arg,Orn,Leu,Phe, 0.814; Asn,Ala,Met,Ile,Phe,Trp, 0.814; Ser,Asn,Gly,Ala,Tyr,Trp, 0.813; Gln,Ala,Cit,Tyr,Met,Leu, 0.813; Ser,Asn,Gly,Ala,Pro,ABA, 0.813; Ala,Cit,Pro,Met,Orn,Phe, 0.813; Thr, Ala, Cyt, Pro, Tyr, Orn, 0.813; Ser, Gly, Ala, Arg, Pro, Met, 0.811; Ala,Cit,Pro,Met,Ile,Leu, 0.811; Glu, Ser, Asn, His, Ala, Arg, 0.811; Ser, Gly, His, Ala, Lys, Trp, 0.811; Ser,Gly,Ala,Met,Lys,Ile, 0.811; Ser, Gly, Gln, Ala, ABA, Trp, 0.811; Ser,Gly,His,Ala,Ile,Trp, 0.811; Thr,Ala,Arg,ABA,Ile,Leu, 0.81; Ala, Cyt, Met, Orn, Ile, Phe, 0.81; Ser, Gly, Gln, Ala, Arg, Phe, 0.81; Asn, Gln, Ala, ABA, Met, Trp, 0.81; Ser,Gly,Thr,Ala,Cyt,Ile, 0.81; Ser, His, Thr, Ala, Cyt, Lys, 0.81; Glu, Ser, Asn, Gly, Ala, Cyt, 0.81; His, Ala, Cyt, Tyr, Met, Leu, 0.808; Gln, Ala, Cyt, ABA, Ile, Leu, 0.808; Thr, Ala, Arg, Pro, ABA, Lys, 0.808; Ser,Gly,Ala,Tyr,Met,Orn, 0.808; Thr, Ala, Arg, ABA, Tyr, Val, 0.808; Ser,Gly,Ala,Arg,Met,Orn, 0.807; Thr,Ala,Arg,Tyr,Ile,Leu, 0.807; Glu,Ser,Thr,Ala,Arg,Leu, 0.807; Glu,Asn,His,Ala,Pro,Trp, 0.807; Asn,Ala,Val,Met,Ile,Leu, 0.807; Glu,Ser,Ala,Arg,ABA,Phe, 0.805; Ser,Gly,Thr,Ala,ABA,Trp, 0.805; Ser,Thr,Ala,Arg,Lys,Trp, 0.805; Ser,His,Ala,Met,Lys,Trp, 0.805; Ser,Gly,Ala,Cit,ABA,Trp, 0.803; Glu,Ser,Ala,Arg,Val,Leu, 0.803; Glu,Ser,Gln,Ala,Met,Trp, 0.802; Ala,Pro,Tyr,Met,Ile,Trp, 0.802; Glu,Ser,Ala,Arg,Tyr,Phe, 0.8; Ser,Asn,Ala,ABA,Leu,Trp, 0.8; Ser,Asn,Ala,ABA,Val,Trp, 0.8; Ser,Ala,Val,Ile,Leu,Phe, 0.8; Ser,His,Ala,Cit,Orn,Leu, 0.793.

[0178] [206. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment] Ala,hTrp, 0.83; Ala,Arg, 0.825; Ala, hKyn, 0.824; Ala,Serot, 0.82; Asn,Ala, 0.819; His,Ala, 0.819; Ala,It, 0.817; No,No, 0.817; Ala,Pro, 0.817; Gln,Ala, 0.817; Ala,Val, 0.817; Ala,Lys, 0.817; Ala,Met, 0.816; Ala,NP, 0.816; Ala,Trp, 0.816; Ala,XA, 0.816; Ala,Tyr, 0.814; His,hTrp, 0.786; Pro,hTrp, 0.783; His,hKyn, 0.779; Asn,hTrp, 0.762; Lys,hTrp, 0.759; Pro,hKyn, 0.752; Lys,hKyn, 0.752; Arg,hTrp, 0.748; Lys,Serot, 0.748; His,Pro, 0.746; Arg,Pro, 0.745; Arg,Serot, 0.741; Pro,Trp, 0.738; Arg,Trp, 0.738; Trp,hTrp, 0.737; hKyn,XA, 0.735; Lys,Trp, 0.734; Trp,hKyn, 0.729; Trp,Serot, 0.729; His,Trp, 0.726; Lys,XA, 0.726; Thr,Pro, 0.726; His,Arg, 0.726; Val,hKyn, 0.723; Asn,Pro, 0.723; met,hTrp, 0.721; Gln,Lys, 0.721; His,Lys, 0.721; Pro,Val, 0.721; Arg,hKyn, 0.72; Pro,NP, 0.72; Arg,Tyr, 0.72; Val,Lys, 0.72; Gln,hTrp, 0.72; His,Tyr, 0.72; Asn,Trp, 0.717; Thr,Lys, 0.715; Thr,Trp, 0.714; Pro,Serot, 0.712; Pro,Tyr, 0.712; Arg,NP, 0.712; Pro,Met, 0.712; Thr,hTrp, 0.711; Arg,XA, 0.711; Arg,Ile,0.711; Gln,Pro, 0.711; Tyr,Lys, 0.709; Val,Trp, 0.709; Arg,Lys, 0.707; Thr,hKyn, 0.707; Tyr,Trp, 0.707; Lys,Ile, 0.707; Asn,Arg, 0.707; Trp,NP, Asn,Lys, 0.706; Ile,hTrp, 0.704; Met,Trp, 0.704; Gln,Trp, 0.703; Met,Lys, 0.703; Tyr,hTrp, 0.701; Gln,Arg, 0.701; Tyr, Serot, 0.7; Cit,Trp, 0.698; Val,hTrp, 0.698; Cit,Arg, 0.698; Arg,Met, 0.698; Tyr,hKyn, 0.697; Ile,hKyn, 0.697; Met,hKyn, 0.697; Met,Serot, 0.692; Cit,Pro, 0.681; hTrp,XA, 0.675; Asn,Tyr, 0.675; hTrp,Serot, 0.672; hKyn,Serot, 0.67; hTrp,NP, 0.67; Tyr,NP, 0.663.

[0179] [207. Three-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment] Ala,hTrp,Porture, 0.854; Gln,Ala,hTrp, 0.841; Ala,Arg,Serot, 0.836; Ala,Pro,hTrp, 0.834; Ala,hTrp,NP, 0.833; Ala,Arg,Met, 0.833; Ala,Arg,hTrp, 0.831; Ala,Lys,hTrp, 0.831; Ala,Tyr,hTrp, 0.831; Ala,Cit,hTrp, 0.83; Ala,Val,hTrp, 0.83; Ala,Lys,hKyn, 0.83; Ala,hKyn,hTrp, 0.828; Ala,Trp,hTrp, 0.828; Asn,Ala,Arg, 0.828; Ala,hTrp,XA, 0.827; Ala,Trp,hKyn, 0.827; Ala,Met,hKyn, 0.827; Thr,Ala,hKyn, 0.827; Ala,Arg,Val, 0.827; His,Ala,hTrp, 0.825; Ala,Met,Serot, 0.825; Ala,Arg,Lys, 0.825; Ala,Arg,XA, 0.825; Ala,Arg,Pro, 0.825; Ala,Cit,hKyn, 0.824; Ala,Cit,Met, 0.824; Asn,Ala,Cit, 0.824; His,Ala,NP, 0.824; Ala,Arg,Ile, 0.824; Ala,Arg,Tyr, 0.824; His,Ala,hKyn, 0.822; Ala,Pro,Snap, 0.822; Gln,Ala,hKyn, 0.822; Ala,Met,hTrp, 0.82; His,Ala,Serot, 0.82; Ala,Tyr,Serot, 0.82; Ala,Lys,Serot, 0.82; Ala,Cit,Arg, 0.82; His,Ala,Pro, 0.82; Gln,His,Ala, 0.82; Ala,Val,Serot, 0.819; His,Ala,Met, 0.819; Gln,Ala,Arg, 0.819; Asn,Gln,Ala, 0.819; His,Ala,Tyr, 0.819; His,Ala,Val, 0.819; His,Ala,XA, 0.819; Thr,Ala,hTrp,0.817; Asn, Ala, hTrp, 0.817; Thr, Ala, Serot, 0.817; Ala, Ile, Serot, 0.817; Ala,Met,Trp, 0.817; Ala,Met,NP, 0.817; Ala,Arg,NP, 0.817; Asn, Ala, XA, 0.817; Ala,Met,Lys, 0.817; Ala,Cit,Trp, 0.817; Ala,Pro,NP, 0.817; Ala,Cit,Val, 0.817; Ala,Cit,Lys, 0.817; His, Ala, Ile, 0.817; Ala,Ile,Trp, 0.817; Ala,Trp,XA, 0.817; Gln, Ala, Tyr, 0.817; Ala,hKyn,XA, 0.816; Ala, Trp, Serot, 0.816; Asn, Ala, Tyr, 0.816; Gln,Thr,Ala, 0.816; Ala, Tyr, Trp, 0.816; Gln, Ala, Ile, 0.816; Thr,Ala,Arg, 0.814; Asn, Ala, NP, 0.814; His, Ala, Cit, 0.814; Ala, Val, Met, 0.814; Ala,Pro,Met, 0.814; Ala,XA,NP, 0.814; Ala,Cit,Tyr, 0.814; Ala,Cit,Pro, 0.814; Thr,Ala,XA, 0.814; Gln, Ala, Trp, 0.814; Ala, Val, Ile, 0.814; Ala,Pro,Ile, 0.814; Asn,Ala,Trp, 0.813; Ala,Cit,NP, 0.813; Ala,Ile,NP, 0.813; Ala,Trp,NP, 0.813; Ala,Tyr,NP, 0.813; Asn,His,Ala, 0.811; Asn,Ala,Ile, 0.811; Ala,Cit,Ile, 0.811; Ala,Lys,Trp, 0.811; Thr,Ala,NP, 0.81; Thr,Ala,Val, 0.81; Pro,hKyn,XA, 0.808; His,Thr,Ala, 0.808; Ala,Tyr,Met, 0.807; Pro,hKyn,hTrp, 0.802; Thr,Ala,Tyr, 0.8; Thr,Ala,Ile, 0.799.

[0180] [208. Equation of four variables derived from amino acids and amino acid-related metabolites before the start of treatment] Ala,Cit,hTrp,Serot, 0.865; Ala,Pro,hTrp,Snatch, 0.859; Ala,hKyn,hTrp,Serot, 0.858; Ala,Val,hTrp,Serot, 0.854; Ala,hTrp,Serot,NP, 0.854; Ala,Tyr,hTrp,Serot, 0.854; Thr,Ala,hTrp,Serot, 0.853; Ala,hTrp,Serot,XA, 0.853; Ala,Ile,hTrp,Clasp, 0.853; Ala,Trp,hTrp,Serot, 0.853; His,Ala,hTrp,Serot, 0.85; Ala,Met,hTrp,Chet, 0.85; Ala,Lys,hTrp,Serot, 0.85; Gln,Ala,hKyn,hTrp, 0.842; Ala,Cit,Pro,hTrp, 0.842; Ala,Cit,Val,hTrp, 0.841; Asn,Ala,hTrp,Serot, 0.839; Ala,Cit,hTrp,NP, 0.839; Ala,Cit,Lys,hTrp, 0.839; Gln,Ala,hTrp,NP, 0.839; Gln,Ala,Val,hTrp, 0.839; His,Ala,Arg,Serot, 0.839; Ala,Arg,Tyr,Serot, 0.839; Asn,Gln,Ala,hTrp, 0.837; Gln,Ala,Cit,hTrp, 0.837; Ala,Pro,Val,hTrp, 0.837; Ala,Pro,hTrp,NP, 0.837; Ala,Tyr,hKyn,Serot, 0.837; Ala,Arg,Lys,Serot, 0.837; Ala,Arg,Pro,Ceret, 0.837; Ala,Arg,Lys,hTrp, 0.836; Ala,Arg,Serot,XA, 0.836; Ala,Pro,Tyr,hTrp, 0.834; Ala,Pro,Ile,hTrp, 0.834; Gln,Ala,Arg,Serot, 0.834; Ala,Val,hTrp,XA, 0.833; Ala,Arg,hKyn,hTrp, 0.833; Ala,Cit,Tyr,hTrp, 0.833; Gln, Thr, Ala, hTrp, 0.831; Ala,Tyr,hTrp,NP, 0.831; Ala,Tyr,Trp,hTrp, 0.831; Ala,Cit,Ile,hTrp, 0.83; Ala,Met,hTrp,NP, 0.83; Ala,Ile,hTrp,NP, 0.83; Ala,Arg,Met,Ile, 0.83; Ala, Ile, hKyn, hTrp, 0.828; His,Ala,Met,hTrp, 0.828; Ala,Lys,hKyn,hTrp, 0.828; Ala,Ile,hTrp,XA, 0.828; Asn,Ala,Cit,Serot, 0.828; His,Ala,Serot,NP, 0.828; Ala,Cit,Lys,Serot, 0.828; His,Ala,Tyr,hTrp, 0.827; His,Ala,Ile,hTrp, 0.827; His,Ala,Lys,hTrp, 0.827; Ala,Arg,hTrp,XA, 0.827; Ala,Val,Met,hTrp, 0.827; Ala,Met,Serot,NP, 0.827; Ala,Lys,Trp,Serot, 0.827; Asn,Ala,hTrp,NP, 0.825; Ala,Met,Lys,hTrp, 0.825; Ala,Met,Trp,hKyn, 0.825; Asn,Ala,HKyn,XA, 0.824; Asn,Ala,Pro,Serot, 0.824; Asn,Ala,Trp,HKyn, 0.824; Thr,Ala,Lys,Serot, 0.824; Thr,Ala,Trp,Serot, 0.822; Asn,Gln,Ala,Serot, 0.822; Asn,Ala,Tyr,HKyn, 0.822; Gln,His,Ala,hKyn, 0.822; Thr,Ala,HKyn,hTrp, 0.82; Thr,Ala,Pro,hTrp, 0.82; Ala,Tyr,Met,hTrp, 0.82; Thr,Ala,Val,hTrp, 0.82; His,Ala,Val,hKyn, 0.82; Ala,Tyr,Met,hKyn, 0.82; Ala,Pro,I,hKyn, 0.82; Gln,His,Ala,Serot, 0.82; Asn, His, Ala, hTrp, 0.819; Asn,Ala,Trp,hTrp, 0.819; Thr,Ala,Met,Serot, 0.819; Ala,Val,Met,hKyn, 0.819; Thr,Ala,Met,hTrp, 0.817; Asn,Ala,Lys,hTrp, 0.817; Thr,Ala,Serot,NP, 0.817; Gln,Thr,Ala,Serot, 0.817; Ala,Lys,Ile,hKyn, 0.817; Gln,Ala,Cit,hKyn, 0.816; Gln,Ala,Trp,Serot, 0.816; Ala,Val,Trp,Serot, 0.816; Thr,Ala,Trp,hTrp, 0.814; Gln,Ala,hKyn,XA, 0.814; Thr,Ala,Pro,Serot, 0.814; Ala,Arg,Ile,hKyn, 0.814; Ala,Trp,Serot,NP, 0.814; Ala,Tyr,hKyn,XA, 0.813; Thr,Ala,Ile,Serot, 0.811; Thr,Ala,Tyr,Serot, 0.811; Gln,Ala,Ile,hKyn, 0.811; Thr,Ala,Tyr,hTrp, 0.808.

[0181] [209. Five-variable equation derived from amino acids and amino acid-related metabolites before treatment started] Ala,Cit,hKyn,hTrp,Serot, 0.87; Gln,Ala,Cit,hTrp,Serot, 0.865; Ala,Cit,Arg,hTrp,Serot, 0.865; Ala,Cit,Tyr,hTrp,Serot, 0.865; Ala,hKyn,hTrp,Serot,XA, 0.864; His,Ala,Pro,hTrp,Serot, 0.864; Ala,Arg,hKyn,hTrp,Serot, 0.864; Ala,Arg,Met,hTrp,Serot, 0.862; Ala,Cit,Val,hTrp,Serot, 0.861; His,Ala,hKyn,hTrp,Serot, 0.859; Ala,Pro,Tyr,hTrp,Serot, 0.859; Ala,Pro,Lys,hTrp,Serot, 0.858; Ala,hTrp,Serot,XA,NP, 0.856; Ala,Val,hTrp,Serot,NP, 0.856; Ala,Tyr,Ile,hTrp,Serot, 0.856; Thr,Ala,Pro,hTrp,Serot, 0.854; His,Ala,hTrp,Serot,XA, 0.854; Thr,Ala,Cit,hTrp,Serot, 0.853; Asn,Ala,Cit,hTrp,Serot, 0.853; His,Ala,Tyr,hTrp,Serot, 0.853; Thr,Ala,Met,hTrp,Serot, 0.851; Thr,Ala,hTrp,Serot,XA, 0.85; Ala,Trp,hTrp,Serot,XA, 0.85; Pro,Val,hKyn,hTrp,XA, 0.85; Ala,Met,hTrp,Serot,XA, 0.848; Thr,Ala,Trp,hTrp,Serot, 0.845; Thr,Ala,Tyr,hTrp,Serot, 0.844; Asn,His,Ala,hTrp,Serot, 0.844; Gln,His,Ala,Arg,hTrp, 0.842; Gln,His,Ala,Tyr,HTrp, 0.842; Gln,Ala,Arg,HKyn,HTP, 0.842; Ala,Arg,Tyr,Met,Serot,0.842; Ala,Val,Met,hKyn,Serot, 0.842; Gln,Ala,Ile,hTrp,XA, 0.841; Thr,Ala,Arg,Met,Serot, 0.841; His,Ala,Cit,Met,hTrp, 0.839; Ala,Arg,Tyr,Lys,hTrp, 0.839; Ala, Met, hKyn, Serot, XA, 0.839; Ala, Lys, HKyn, Serot, XA, 0.839; Ala,Cit,Arg,Met,Serot, 0.839; His,Ala,Tyr,hKyn,Serot, 0.839; Asn,Ala,Pro,hKyn,hTrp, 0.837; His,Ala,Tyr,Val,hTrp, 0.837; Gln,Ala,Val,Met,hTrp, 0.837; Ala,Pro,Lys,Ile,hTrp, 0.837; Thr,Ala,Arg,Serot,XA, 0.837; His,Ala,Met,hKyn,Serot, 0.837; Ala,Lys,hTrp,XA,NP, 0.836; Ala,Pro,Trp,hTrp,NP, 0.836; Gln,Ala,Ile,hTrp,NP, 0.836; Thr,Ala,Arg,Tyr,Serot, 0.836; Ala,Val,hKyn,Serot,XA, 0.836; Asn,Ala,Arg,Pro,Serot, 0.836; Gln,Ala,Met,Trp,hTrp, 0.834; Ala,Tyr,Lys,hTrp,NP, 0.834; Thr,Ala,Cit,Arg,Serot, 0.834; Thr,Ala,Cit,HKyn,hTrp, 0.833; Thr,Ala,Cit,hTrp,NP, 0.833; His,Ala,Pro,Tyr,hTrp, 0.833; Gln,Ala,Arg,Met,hTrp, 0.833; Ala,Cit,Trp,hTrp,NP, 0.833; Ala,Tyr,Trp,HKyn,hTrp, 0.833; Ala,Arg,Pro,Ile,hTrp, 0.833; Asn,Ala,Cit,HKyn,Serot, 0.833; Thr,Ala,hKyn,Serot,XA, 0.833; No, Ile, hKyn, Serot, XA, 0.833; Ala,Tyr,HKyn,Serot,XA, 0.833; His,Ala,Pro,hTrp,NP, 0.831; Ala,Arg,Met,hTrp,NP, 0.831; His,Ala,Val,Met,hTrp, 0.831; Ala,Lys,Trp,hTrp,NP, 0.831; Ala,Val,hKyn,hTrp,XA, 0.83; His,Ala,Pro,Lys,hTrp, 0.83; Ala,Pro,Val,Ile,hTrp, 0.83; Ala,Tyr,Val,hKyn,hTrp, 0.83; Ala,Pro,Val,Met,hTrp, 0.83; Asn,Ala,Pro,Met,hTrp, 0.828; Ala,Met,Trp,hTrp,NP, 0.828; Ala,Cit,hKyn,Serot,XA, 0.828; Asn,His,Ala,Arg,hTrp, 0.827; Ala,Val,Met,hKyn,hTrp, 0.827; Ala,Lys,Trp,hTrp,XA, 0.827; Ala,Val,Met,Trp,hTrp, 0.827; Thr,Ala,Met,hTrp,NP, 0.825; Asn,Ala,Val,Met,hTrp, 0.825; Asn,His,Ala,Cit,Serot, 0.825; Ala,Tyr,Met,HKyn,XA, 0.825; Thr,Ala,Cit,hTrp,XA, 0.822; Thr,Ala,Val,Met,hTrp, 0.822; Asn,Ala,hTrp,XA,NP, 0.82; Asn,Ala,Ile,Trp,hTrp, 0.82; Ala,Cit,Met,Ile,hKyn, 0.819; Thr,Ala,hTrp,XA,NP, 0.817; Asn,His,Ala,Ile,hTrp, 0.817; Thr,Ala,Pro,Lys,hTrp, 0.816; Asn,Ala,Tyr,hTrp,XA, 0.814; Ala,Pro,Met,Ile,hTrp, 0.813; Asn,His,Ala,Trp,Serot, 0.813; Thr,Ala,Ile,Trp,hTrp, 0.81; Thr,Ala,Tyr,Trp,hTrp, 0.808.

[0182] [210. Equation of six variables derived from amino acids and amino acid-related metabolites before the start of treatment] His,Ala,Arg,hTrp,Serot,XA, 0.865; Ala,Cit,Val,hKyn,hTrp,Serot, 0.865; Ala,Cit,Pro,hTrp,Serot,XA, 0.865; Gln,Thr,Ala,Arg,hTrp,Serot, 0.862; Thr,Ala,Cit,hKyn,hTrp,Serot, 0.862; Ala,Arg,Pro,Met,hTrp,Serot, 0.862; Asn,His,Ala,Arg,hTrp,Serot, 0.861; Ala,Cit,Met,Lys,hTrp,Serot, 0.859; Ala,Arg,Tyr,Trp,hTrp,Serot, 0.859; Ala,Pro,Tyr,hTrp,Serot,NP, 0.859; Thr,Ala,Arg,Ile,HTrp,Serot, 0.858; Ala,Cit,Arg,HKyn,hTrp,Serot, 0.858; Gln,Ala,Lys,HKyn,HTrp,Serot, 0.858; Gln, Thr, Ala, Ile, hTrp, Serot, 0.856; Ala,Val,hKyn,hTrp,Serot,XA, 0.856; Ala,Tyr,Val,Trp,hTrp,Serot, 0.856; Thr,Ala,Arg,Pro,hTrp,Serot, 0.854; Ala, Met, Lys, hKyn, hTrp, Serot, 0.854; Thr,Ala,hTrp,Serot,XA,NP, 0.853; Thr,Ala,Trp,HKyn,hTrp,Serot, 0.853; Asn,Ala,Trp,HKyn,hTrp,Serot, 0.853; Ala,Met,Trp,hTrp,Serot,XA, 0.853; Ala,Val,Ile,hTrp,Serot,NP, 0.853; Thr,Ala,Arg,Met,hTrp,Serot, 0.851; Ala,Tyr,Met,hKyn,hTrp,Serot, 0.851; Asn,Gln,Ala,Val,hTrp,Serot, 0.851; His,Ala,Lys,hTrp,Serot,NP, 0.851; His,Ala,Pro,HKyn,HTrp,XA,0.85; Ala,Met,Lys,Trp,hTrp,Serot, 0.85; Ala,Lys,Trp,hTrp,Serot,NP, 0.85; Thr,Ala,Arg,Val,hTrp,Serot, 0.848; Ala,Arg,Met,Ile,hTrp,Ceret, 0.848; Thr, Ala, Ile, hKyn, hTrp, Serot, 0.848; Ala,Pro,Met,Trp,hTrp,Serot, 0.848; His,Thr,Ala,Arg,Ile,Serot, 0.848; Ala,Lys,Ile,Trp,hTrp,Serot, 0.848; Ala, Arg, Met, Ile, hKyn, Serot, 0.848; Gln,Ala,Pro,Val,hTrp,XA, 0.848; Ala,Tyr,Met,hTrp,Serot,NP, 0.847; Ala,Cit,Tyr,Met,hKyn,hTrp, 0.847; His,Thr,Ala,Ile,hTrp,Serot, 0.845; Ala,Cit,Arg,Tyr,Met,hTrp, 0.845; Asn,Ala,Cit,Tyr,HKYN,HTrp, 0.845; Thr,Ala,Ile,hTrp,Serot,XA, 0.844; Asn,Thr,Ala,Arg,Ile,Set, 0.844; Gln,Ala,Cit,Met,HKyn,hTrp, 0.844; His,Ala,Arg,Pro,Ile,hTrp, 0.844; Ala,Cit,Pro,hTrp,XA,NP, 0.844; Asn,Gln,Ala,Pro,HKyn,hTrp, 0.842; Thr,Ala,Met,Ile,hTrp,Serot, 0.841; Asn,Ala,Lys,hTrp,Serot,XA, 0.841; Asn,Gln,His,Thr,Ala,hTrp, 0.841; Asn,Ala,Cit,Met,hKyn,hTrp, 0.841; Asn,Gln,Ala,Val,hTrp,XA, 0.841; Thr,Ala,Ile,Trp,hTrp,Serot, 0.839; Ala,Arg,Lys,HKyn,HTrp,XA, 0.839; No, Cit, Val, I, hTrp, XA, 0.839; Ala,Pro,Tyr,Val,hTrp,XA, 0.839; Asn,Thr,Ala,Arg,Val,Serot, 0.839; Thr,Ala,Arg,Tyr,Ile,Serot, 0.839; His,Ala,Cit,Arg,Ile,hTrp, 0.837; Gln,Thr,Ala,Arg,Ile,Serot, 0.837; His,Ala,Met,Lys,hKyn,hTrp, 0.836; Thr,Ala,Arg,Ile,Pick,NP, 0.836; Thr,Ala,Arg,Val,Met,Serot, 0.836; Asn,Ala,Cit,Arg,hTrp,NP, 0.836; Ala,Pro,Val,Ile,Trp,hTrp, 0.836; Ala,Met,Ile,hTrp,Serot,NP, 0.834; Thr,Ala,Cit,Met,hTrp,NP, 0.834; Thr,Ala,Cit,Arg,hTrp,NP, 0.834; Asn, Gln, Ala, Ile, hKyn, hTrp, 0.834; Thr,Ala,Arg,Val,Ile,Serot, 0.834; Asn,His,Ala,Pro,Val,hTrp, 0.834; Asn,His,Ala,Lys,HKyn,Serot, 0.834; His,Thr,Ala,Cit,Lys,hTrp, 0.833; Thr,Ala,Cit,Arg,Met,hTrp, 0.833; Ala,Cit,Trp,HKyn,hTrp,XA, 0.831; His,Ala,Lys,hTrp,XA,NP, 0.831; Ala,Arg,Trp,HKyn,HTrp,XA, 0.83; Thr,Ala,Cit,Arg,Trp,hTrp, 0.828; Ala,Tyr,Val,Ile,hKyn,hTrp, 0.828; Ala,Val,Ile,Trp,hTrp,XA, 0.828; Thr,Ala,Cit,Pro,Lys,hTrp, 0.827; Thr,Ala,Arg,Tyr,Val,hTrp, 0.827; Asn,His,Ala,Pro,hTrp,XA, 0.827; His,Ala,Val,Met,hTrp,XA, 0.825; His, Thr, Ala, Met, hKyn, hTrp, 0.822; Asn,Thr,Ala,Arg,Tyr,hTrp, 0.822; His,Thr,Ala,Tyr,hKyn,hTrp, 0.82; Thr,Ala,Arg,Lys,Trp,hTrp, 0.82; Thr,Ala,Arg,Val,Ile,hTrp, 0.819; Thr,Ala,Arg,Ile,hKyn,hTrp, 0.819; Thr,Ala,Cit,Lys,hTrp,XA, 0.819; His,Thr,Ala,Trp,hTrp,NP, 0.819; Asn,Ala,Val,Ile,Trp,hTrp, 0.816; His,Thr,Ala,Tyr,Trp,hTrp, 0.816; Asn,His,Ala,Met,hTrp,XA, 0.816; Thr,Ala,Ile,Trp,hTrp,NP, 0.811; Thr,Ala,Ile,Trp,hKyn,hTrp, 0.81; Thr,Ala,Val,Met,Ile,hTrp, 0.808.

[0183] [301. A two-variable formula derived from amino acids before the start of treatment with PFS as an evaluation index] Arg,Met, 0.784; Arg,Phe, 0.756; Arg,Ile, 0.749; Arg,Leu, 0.743; Thr,Arg, 0.733; Ser,Arg, 0.729; Arg,Orn, 0.727; Cit,Arg, 0.727; His,Arg, 0.727; Arg,Pro, 0.727; Arg,Trp, 0.727; Asn,Arg, 0.725; Gln,Arg, 0.719; Ala,Arg, 0.71; Arg,Lys, 0.71; Tyr,Phe, 0.689; His,Ile, 0.684; Phe,Trp, 0.681; Ser,His, 0.681; His,Phe, 0.679; His,Leu, 0.678; His,Val, 0.676; His,Cit, 0.675; His,Met, 0.673; His,Orn, 0.671; His,Tyr, 0.668; His,Pro, 0.665; Met,Trp, 0.662; His,Thr, 0.657; His,Trp, 0.651; Ser,Thr, 0.651; Gln,His, 0.651; Ser,Ala, 0.649; Ser,Trp, 0.648; Ser,Pro, 0.646; Ala,Phe, 0.644; Asn,His, 0.643; Val,Phe, 0.64; Val,Trp, 0.638; Tyr,Trp, 0.637; Thr,Met, 0.637; Gly,His, 0.635; Thr,Ile, 0.633; Thr,Cit, 0.633; Ala,Met, 0.632; Cit,Trp, 0.632; Leu,Trp, 0.629; Thr,Phe, 0.627; Gly,Trp, 0.627; Ile,Trp, 0.627; Thr,Lys, 0.625; Pro,Trp, 0.625; Orn,Trp, 0.625; Gly,Ala, 0.624; Thr,Pro, 0.624; Ser,Lys, 0.622; Asn,Trp, 0.622; Gly,Lys, 0.621; Ala,Cit, 0.621; Gln,Trp, 0.621; Gln,Ala, 0.619; Ala,Leu, 0.619; His,Lys, 0.619; Thr,Tyr, 0.619; Ala,Ile, 0.617; His,Ala, 0.617; Gly,Thr, 0.617; Thr,Leu, 0.617; Thr,Trp, 0.616; Lys,Ile, 0.614; Ala,Val, 0.613; Gln,Thr, 0.611; Ser,Asn, 0.608; Asn,Thr, 0.608; Ala,Trp, 0.606; Lys,Trp, 0.606; Leu,Phe, 0.606; Ala,Pro, 0.603; Asn,Ala, 0.603; Pro,Phe, 0.602; Pro,Lys, 0.6; Lys,Leu, 0.598; Ala,Tyr, 0.594; Asn,Phe, 0.594; Ala,Lys, 0.592; Gln,Lys, 0.579; Met,Phe, 0.575; Met,Lys, 0.57; Tyr,Lys, 0.567; Gly,Met, 0.557; Gly,Pro, 0.543; Gly,Leu, 0.543; Gly,Ile, 0.54.

[0184] [302. A three-variable formula derived from amino acids before the start of treatment with PFS as an evaluation index] His,Arg,Met, 0.789; Cit,Arg,Met, 0.786; Arg,Pro,Met, 0.786; Arg,Val,Met, 0.783; Arg,Met,Ile, 0.781; Ala,Arg,Met, 0.776; Ser,Arg,Phe, 0.77; Arg,Met,Leu, 0.768; Gln,Arg,Met, 0.768; Gly,Arg,Met, 0.765; Thr,Arg,Phe, 0.765; His,Arg,Phe, 0.76; Arg,Val,Phe, 0.759; Arg,Ile,Phe, 0.756; Gln,Arg,Phe, 0.756; Ser,Thr,Arg, 0.751; Thr,Arg,Ile, 0.749; Arg,Val,Ile, 0.749; Arg,Ile,Trp, 0.749; Gly,Arg,Ile, 0.748; Ala,Arg,Phe, 0.748; Cit,Arg,Leu, 0.746; Asn,Arg,Phe, 0.746; Arg,Ile,Leu, 0.744; Thr,Arg,Trp, 0.743; Thr,Cit,Arg, 0.743; Gln,Arg,Ile, 0.743; Arg,Lys,Phe, 0.743; Cit,Arg,Val, 0.741; Asn,Arg,Ile, 0.741; Arg,Val,Leu, 0.74; Ser,Arg,Ile, 0.738; Asn,Arg,Val, 0.737; Gln,Arg,Leu, 0.737; Arg,Pro,Ile, 0.735; His,Arg,Ile, 0.735; His,Cit,Arg, 0.732; His,Thr,Arg, 0.732; Arg,Pro,Val, 0.732; Gly,Arg,Val, 0.732; Gly,Arg,Leu, 0.732; Cit,Arg,Pro, 0.73; Asn,Gly,Arg, 0.729; Gly,Cit,Arg, 0.729; His,Arg,Val, 0.729; Asn,Cit,Arg, 0.727; Gly,Gln,Arg, 0.727; Asn, Arg, Orn, 0.725; Thr,Arg,Orn, 0.725; Ala,Arg,Leu, 0.725; Arg,Tyr,Val, 0.724; Cit,Arg,Lys, 0.722; Gln,Cit,Arg, 0.722; Arg,Orn,Trp, 0.721; Ser,Arg,Orn, 0.721; Ser,Gly,Arg, 0.721; Arg,Orn,Leu, 0.721; Gly,Arg,Trp, 0.719; His,Arg,Leu, 0.719; Ser,Arg,Lys, 0.717; His,Arg,Orn, 0.714; Thr,Arg,Tyr, 0.711; Ala,Arg,Trp, 0.706; Gln,Arg,Orn, 0.705; His,Ala,Arg, 0.705; Gln,Arg,Tyr, 0.702; His,Val,Phe, 0.684; His,Arg,Tyr, 0.684; Ile,Phe,Trp, 0.681; Leu,Phe,Trp, 0.679; Arg,Tyr,Trp, 0.679; Ser,Phe,Trp, 0.675; Gly,Phe,Trp, 0.67; Pro,Val,Phe, 0.662; Ala,Phe,Trp, 0.66; Ala,Val,Phe, 0.66; Ala,Orn,Phe, 0.659; Lys,Phe,Trp, 0.657; Ala,Cit,Phe, 0.657; Gln,Phe,Trp, 0.656; Cit,Lys,Phe, 0.654; Gly,Val,Phe, 0.651; Thr,Ala,Phe, 0.651; Ser,Gly,Ala, 0.648; Ala,Pro,Phe, 0.644; Asn,Ala,Phe, 0.644; Ala,Tyr,Trp, 0.64; Thr,Lys,Phe, 0.64; Pro,Lys,Phe, 0.64; Ala,Tyr,Phe, 0.638; Gly,Ala,Phe, 0.635; Gly,Ala,Trp, 0.63; Gly,Ala,Pro, 0.629; Asn,Gly,Ala, 0.627; Val,Lys,Phe, 0.627; Gly,Ala,Orn, 0.625; Gly,Lys,Phe, 0.625; Gly,His,Ala, 0.622; Ser,Ala,Tyr, 0.619; Gln,Ala,Tyr, 0.587.

[0185] [303. A four-variable formula derived from amino acids before the start of treatment with PFS as an evaluation index] Cit,Arg,Met,Phe, 0.787; His,Arg,Met,Orn, 0.783; Gly,Arg,Met,Trp, 0.783; Asn,Arg,Met,Trp, 0.781; Ala,Arg,Met,Leu, 0.781; His,Arg,Met,Phe, 0.781; Thr,Arg,Met,Phe, 0.775; Thr,Cit,Arg,Phe, 0.771; His,Cit,Arg,Phe, 0.771; Ser,Ala,Arg,Met, 0.771; Arg,Met,Ile,Phe, 0.77; Gln,Arg,Met,Phe, 0.768; Cit,Arg,Ile,Phe, 0.767; Cit,Arg,Tyr,Phe, 0.767; Arg,Met,Lys,Trp, 0.765; Gly,Cit,Arg,Phe, 0.765; Thr,Arg,Ile,Phe, 0.765; Gln,Ala,Arg,Met, 0.765; Ala,Arg,Met,Phe, 0.765; Cit,Arg,Val,Phe, 0.762; His,Thr,Arg,Phe, 0.76; Arg,Val,Ile,Phe, 0.76; Ser,Arg,Met,Lys, 0.759; His,Arg,Ile,Phe, 0.759; Arg,Tyr,Ile,Phe, 0.757; Arg,Pro,Leu,Phe, 0.756; Asn,Arg,Met,Lys, 0.754; Gln,Arg,Val,Phe, 0.754; Ser,Arg,Val,Phe, 0.752; Gly,Arg,Phe,Trp, 0.752; Thr,Ala,Arg,Phe, 0.752; Thr,Arg,Met,Lys, 0.751; His,Arg,Lys,Phe, 0.751; Gln,Ala,Arg,Phe, 0.751; Ala,Arg,Lys,Phe, 0.751; Ala,Arg,Pro,Phe, 0.751; Arg,Ile,Phe,Trp, 0.749; Arg,Val,Lys,Phe, 0.748; Arg,Tyr,Val,Phe, 0.748; Ala,Arg,Val,Phe, 0.748; Arg,Lys,Ile,Phe, 0.746; Gly,Ala,Arg,Phe, 0.746; Ala,Arg,Phe,Trp, 0.746; His,Arg,Tyr,Phe, 0.741; Gly,Arg,Lys,Phe, 0.741; Cit,Arg,Lys,Phe, 0.74; Gly,Cit,Arg,Tyr, 0.738; Ser,Arg,Lys,Phe, 0.738; Arg,Pro,Tyr,Phe, 0.727; Asn,Arg,Tyr,Phe, 0.722; Cit,Arg,Tyr,Trp, 0.717; Ala,Arg,Tyr,Phe, 0.717; His,Ala,Arg,Tyr, 0.706; Ser,Silver,Tyr,Orange, 0.705; Arg,Tyr,Phe,Trp, 0.705; Ala,Arg,Pro,Tyr, 0.7; His,Arg,Tyr,Orn, 0.698; Ala,Arg,Tyr,Ile, 0.698; Ala,Arg,Tyr,Leu, 0.694; Ala,Arg,Tyr,Lys, 0.69; Gly,Ala,Arg,Tyr, 0.69; Copper,Silver,Tyr,Orn, 0.689; Gln,Ala,Arg,Tyr, 0.689; Gln,Silver,Tyr,Iron, 0.687; Arg,Tyr,Ile,Trp, 0.686; Ala,Ile,Leu,Phe, 0.681; Gly,Arg,Tyr,Lys, 0.678; Ala,Cit,Val,Phe, 0.678; Ala,Orn,Leu,Phe, 0.676; Ala,Cit,Leu,Phe, 0.676; Ser,Ala,Leu,Phe, 0.675; Ala,Val,Ile,Phe, 0.675; Ser,Ala,Orn,Phe, 0.671; His,Ala,Orn,Phe, 0.668; Ala,Met,Phe,Trp, 0.662; Gln,Ala,Orn,Phe, 0.662; Ser,Ala,Phe,Trp, 0.662; His,Ala,Cit,Phe, 0.659; Thr,Ala,Met,Phe, 0.657; His,Ala,Met,Phe, 0.656; Ala,Pro,Orn,Phe, 0.656; Ser,Ala,Pro,Phe, 0.654; Thr,Ala,Leu,Phe,0.654; His,Thr,Ala,Phe, 0.652; Ala,Cit,Lys,Phe, 0.652; Gln,Ala,Phe,Trp, 0.651; Ala,Cit,Tyr,Phe, 0.651; Gly,Thr,Ala,Phe, 0.649; Asn,Gln,Ala,Phe, 0.644; Ser,Ala,Tyr,Phe, 0.644; Ala,Tyr,Leu,Phe, 0.641; Ala,Pro,Tyr,Phe, 0.64; Ala,Pro,Met,Phe, 0.64; Ala,Lys,Ile,Phe, 0.64; Gln,Ala,Tyr,Phe, 0.637; Gln,Ala,Ile,Phe, 0.637; Gly,Ala,Pro,Phe, 0.635; Gly,Ala,Lys,Phe, 0.635; Gly,Ala,Tyr,Phe, 0.624; Ala,Tyr,Ile,Phe, 0.622.

[0186] [304. A five-variable formula derived from amino acids before the start of treatment with PFS as an evaluation index] His,Cit,Arg,Met,Phe, 0.802; His,Arg,Val,Met,Phe, 0.794; Ala,Arg,Ile,Leu,Phe, 0.783; Ala,Arg,Val,Met,Phe, 0.781; His,Ala,Arg,Met,Ile, 0.779; Thr,Arg,Val,Met,Phe, 0.776; Gly,Ala,Arg,Met,Leu, 0.776; Arg,Tyr,Val,Met,Phe, 0.775; Arg,Met,Ile,Phe,Trp, 0.775; Ser,Ala,Arg,Val,Met, 0.775; Arg,Val,Met,Phe,Trp, 0.775; Thr,Arg,Met,Phe,Trp, 0.773; Ser,Thr,Ala,Arg,Met, 0.773; Ala,Cit,Arg,Met,Phe, 0.773; Gly,Ala,Cit,Arg,Met, 0.771; His,Ala,Arg,Pro,Met, 0.77; Arg,Val,Met,Lys,Phe, 0.77; Ala,Arg,Met,Lys,Phe, 0.77; His,Ala,Arg,Val,Met, 0.768; Ser,Thr,Arg,Phe,Trp, 0.768; Cit,Arg,Val,Ile,Phe, 0.768; Thr,Ala,Arg,Met,Phe, 0.768; Arg,Val,Met,Orn,Phe, 0.767; Ala,Arg,Val,Met,Trp, 0.765; Asn,Ala,Arg,Met,Phe, 0.765; His,Ala,Arg,Val,Phe, 0.763; Asn,Gln,Ala,Arg,Met, 0.762; Arg,Val,Met,Leu,Phe, 0.762; Thr,Ala,Arg,Met,Orn, 0.76; Asn,Arg,Val,Ile,Phe, 0.76; Thr,Ala,Arg,Phe,Trp, 0.759; Ala,Arg,Met,Orn,Phe, 0.759; Asn,His,Ala,Arg,Phe, 0.754; Ala,Cit,Arg,Ile,Phe, 0.752; His,Ala,Arg,Leu,Phe, 0.752; Ala,Arg,Pro,Lys,Phe, 0.752; Gly,Gln,Ala,Arg,Phe, 0.751; His,Ala,Arg,Ile,Phe, 0.751; Ala,Arg,Lys,Phe,Trp, 0.749; Ala,Cit,Arg,Phe,Trp, 0.749; His,Ala,Arg,Lys,Phe, 0.749; Ser,Ala,Cit,Arg,Phe, 0.746; Arg,Orn,Ile,Phe,Trp, 0.743; Gln,Arg,Orn,Phe,Trp, 0.74; His,Arg,Tyr,Val,Phe, 0.74; Ala,Cit,Arg,Val,Phe, 0.74; Arg,Orn,Leu,Phe,Trp, 0.738; Ala,Cit,Arg,Leu,Phe, 0.738; Thr,Arg,Orn,Lys,Phe, 0.735; His,Ala,Arg,Tyr,Met, 0.729; Ala,Arg,Tyr,Met,Phe, 0.727; Arg,Tyr,Iron,Ile,Phe, 0.724; Cit,Arg,Tyr,Lys,Phe, 0.717; Ala,Arg,Tyr,Val,Phe, 0.714; Gly,His,Ala,Arg,Tyr, 0.713; Ala,Arg,Tyr,Leu,Phe, 0.71; Ser,Asn,Ala,Arg,Tyr, 0.706; Arg,Tyr,Orn,Phe,Trp, 0.706; Ala,Arg,Tyr,Orn,Phe, 0.706; Ala,Arg,Tyr,Lys,Trp, 0.703; Asn,Ala,Cit,Arg,Tyr, 0.703; Arg,Pro,Tyr,Orn,Phe, 0.703; Asn,Ala,Arg,Pro,Tyr, 0.7; Asn,Ala,Arg,Tyr,Val, 0.695; Thr,Ala,Arg,Tyr,Lys, 0.694; Ser,Ala,Ile,Leu,Phe, 0.692; Ala,Pro,Ile,Leu,Phe, 0.69; Ala,Met,Ile,Leu,Phe, 0.69; Gln,Ala,Arg,Tyr,Trp, 0.689; Gln,Ala,Cit,Arg,Tyr, 0.686; Arg,Tyr,Oron,Ile,Trp, 0.684; Ala,Cit,Leu,Phe,Trp,0.679; Gly, Ala, Arg, Tyr, Orn, 0.679; Gln, Ala, Arg, Tyr, Orn, 0.678; Asn, Gly, Ala, Val, Phe, 0.678; Ala,Val,Met,Orn,Phe, 0.676; Thr, Ala, Cyt, Leu, Phe, 0.676; Asn, Thr, Ala, Cit, Phe, 0.675; His, Ala, Orn, Leu, Phe, 0.673; Ala, Val, Orn, Leu, Phe, 0.67; Asn, Thr, Ala, Lys, Phe, 0.668; Asn, Ala, Val, Met, Phe, 0.667; Asn, Gln, Ala, Phe, Trp, 0.667; Thr, Ala, Leu, Phe, Trp, 0.663; His, Ala, Val, Leu, Phe, 0.662; Gln, Ala, Val, Leu, Phe, 0.66; His, Ala, Val, Lys, Phe, 0.659; Ala,Cit,Pro,Phe,Trp, 0.659; Ala,Pro,Val,Met,Phe, 0.657; Gln, Thr, Ala, Cit, Phe, 0.657; Gly,Thr,Ala,Cit,Phe, 0.657; Gly, Gln, Ala, Cit, Phe, 0.656; Gln, Ala, Cit, Pro, Phe, 0.656; Ala,Tyr,Val,Ile,Phe, 0.656; Asn, Ala, Pro, Leu, Phe, 0.654; Gly, Ala, Tyr, Val, Phe, 0.652; Asn, Ala, Lys, Leu, Phe, 0.651; Ala,Cit,Tyr,Orn,Phe, 0.648; Ser, Ala, Tyr, Phe, Trp, 0.638; Gln, Ala, Tyr, Leu, Phe, 0.637.

[0187]

[305] His,Ala,Arg,Met,Leu,Phe, 0.803; Ala,Arg,Met,Ile,Leu,Phe, 0.8; Ala,Arg,Met,Lys,Leu,Phe, 0.797; Thr,Ala,Arg,Met,Leu,Phe, 0.795; Ala,Arg,Val,Met,Leu,Phe, 0.794; Ala,Arg,Met,Leu,Phe,Trp, 0.792; Asn,Ala,Arg,Met,Leu,Phe, 0.792; Gly,Ala,Arg,Met,Leu,Phe, 0.792; Ala,Arg,Met,Orn,Leu,Phe, 0.79; Ala,Arg,Pro,Met,Leu,Phe, 0.786; Ala,Arg,Orn,Ile,Leu,Phe, 0.783; Ala,Arg,Val,Ile,Leu,Phe, 0.783; Ala,Arg,Val,Met,Ile,Phe, 0.783; Gly,Ala,Arg,Pro,Met,Leu, 0.781; Ser,Ala,Arg,Ile,Leu,Phe, 0.779; Gly,Thr,Ala,Arg,Met,Leu, 0.776; His,Thr,Ala,Arg,Val,Phe, 0.773; Ser,Ala,Cit,Arg,Val,Met, 0.771; Ser,Thr,Ala,Arg,Val,Phe, 0.771; Gly,Ala,Arg,Pro,Met,Trp, 0.77; Ser,Asn,Ala,Arg,Val,Met, 0.768; His,Arg,Val,Orn,Ile,Phe, 0.768; Ser,Ala,Arg,Met,Ile,Leu, 0.768; Ser,Asn,Ala,Arg,Met,Orn, 0.767; Ala, Cyt, Arg, Met, Lys, Phe, 0.767; Asn, Ala, Arg, Met, Lys, Phe, 0.767; Ala, Arg, Tyr, Met, Leu, Phe, 0.767; Asn, Ala, Arg, Met, Orn, Trp, 0.765; His, Thr, Ala, Arg, Pro, Phe, 0.762; Gln, Ala, Arg, Met, Ile, Phe, 0.762; Ala, Arg, Val, Ile, Phe, Trp, 0.76; His,Ala,Arg,Met,Ile,Phe, 0.76; Gln,Ala,Cit,Arg,Lys,Phe, 0.759; Ala,Arg,Pro,Met,Ile,Phe, 0.759; Gly,Ala,Arg,Met,Ile,Phe, 0.759; Gly,Thr,Arg,Val,Orn,Phe, 0.757; His,Ala,Arg,Pro,Lys,Phe, 0.757; Gln,Ala,Arg,Pro,Phe,Trp, 0.756; Asn,Ala,Arg,Val,Lys,Phe, 0.754; Gly,Gln,Ala,Arg,Pro,Phe, 0.752; Gly,Ala,Arg,Pro,Lys,Phe, 0.752; Gln,Ala,Arg,Lys,Leu,Phe, 0.751; Thr,Ala,Cit,Arg,Ile,Phe, 0.751; Gln,Thr,Arg,Val,Orn,Phe, 0.749; Ala,Arg,Tyr,Ile,Leu,Phe, 0.749; Ala,Arg,Val,Met,Lys,Ile, 0.748; Ser,Ala,Cit,Arg,Ile,Phe, 0.748; Ala,Cit,Arg,Pro,Phe,Trp, 0.748; Gly,Ala,Arg,Lys,Leu,Phe, 0.746; His,Ala,Arg,Val,Orn,Phe, 0.744; Ser,Gln,Ala,Arg,Ile,Phe, 0.744; Gly,Ala,Arg,Orn,Leu,Phe, 0.743; Gly,Ala,Arg,Val,Leu,Phe, 0.743; Asn,Gly,Ala,Arg,Orn,Phe, 0.743; Ala,Arg,Tyr,Met,Ile,Phe, 0.738; Ser,Ala,Arg,Pro,Ile,Phe, 0.737; Thr,Ala,Cit,Arg,Orn,Phe, 0.737; Ser,Ala,Arg,Pro,Orn,Phe, 0.735; Arg,Val,Orn,Lys,Leu,Phe, 0.732; His,Ala,Arg,Tyr,Met,Phe, 0.727; Asn,Ala,Arg,Tyr,Met,Leu, 0.725; Gly,Ala,Arg,Tyr,Met,Trp, 0.725; Ala,Arg,Pro,Tyr,Val,Met, 0.724; Gln,Ala,Arg,Tyr,Met,Orn, 0.722; Gly,Ala,Cit,Ile,Leu,Phe, 0.722; Thr,Ala,Arg,Tyr,Leu,Phe, 0.722; Ala,Cit,Arg,Pro,Tyr,Phe, 0.719; His,Ala,Cit,Arg,Tyr,Trp, 0.717; Ala,Arg,Pro,Tyr,Val,Phe, 0.717; Ser,Gly,Ala,Arg,Tyr,Phe, 0.716; Ala,Cit,Arg,Tyr,Leu,Phe, 0.716; Ala,Cit,Arg,Tyr,Ile,Leu, 0.713; Asn,Ala,Arg,Tyr,Orn,Phe, 0.713; Asn,Ala,Arg,Tyr,Phe,Trp, 0.711; Asn,Gly,Ala,Arg,Tyr,Val, 0.708; Asn,Ala,Arg,Tyr,Ile,Trp, 0.708; Ser,Asn,Ala,Arg,Tyr,Val, 0.706; Ala,Cit,Tyr,Ile,Leu,Phe, 0.705; Arg,Tyr,Orn,Lys,Ile,Phe, 0.702; Ser,Ala,Arg,Pro,Tyr,Ile, 0.697; Ser,Ala,Arg,Tyr,Ile,Trp, 0.695; Gln,Ala,Arg,Tyr,Val,Trp, 0.695; Gln,Ala,Cit,Arg,Pro,Tyr, 0.687; Asn,Gly,Gln,Ala,Leu,Phe, 0.686; Gln,His,Ala,Cit,Val,Phe, 0.686; Ala,Cit,Val,Ile,Phe,Trp, 0.684; Ala,Cit,Val,Met,Ile,Phe, 0.684; Thr,Ala,Cit,Val,Leu,Phe, 0.683; Asn,Gly,Ala,Val,Lys,Phe, 0.683; Asn,Gly,His,Ala,Val,Phe, 0.678; His,Ala,Cit,Pro,Val,Phe, 0.678; Ala,Cit,Val,Lys,Ile,Phe, 0.678; Asn,Gly,Ala,Pro,Val,Phe, 0.676; Ala,Cit,Tyr,Met,Leu,Phe, 0.675; Asn,Gly,Ala,Pro,Leu,Phe, 0.67; Gly,Ala,Pro,Val,Met,Phe, 0.668; Ser,Ala,Cit,Tyr,Leu,Phe, 0.667; Ala,Cit,Tyr,Leu,Phe,Trp, 0.665; Gln,Ala,Cit,Tyr,Val,Phe, 0.663; Gly,Ala,Tyr,Val,Orn,Phe, 0.656.

[0188] [306. Two-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index] Arg,Met, 0.784; Arg,NP, 0.779; Arg,KynA, 0.77; AnthA,NP, 0.77; hTrp,NP, 0.768; Arg,QA, 0.767; Arg,Kyn, 0.763; QA,NP, 0.76; Kyn,NP, 0.752; His,KynA, 0.74; Arg,AnthA, 0.737; Arg,hTrp, 0.737; Thr,NP, 0.737; Arg,hKyn, 0.737; Thr,Arg, 0.733; hKyn,NP, 0.732; Ser,Arg, 0.729; Arg,Trp, 0.727; Arg,Pro, 0.727; His,Arg, 0.727; Trp,NP, 0.727; Asn,Arg, 0.725; His,QA, 0.725; Gly,Arg, 0.725; His,Kyn, 0.724; Gln,Arg, 0.719; Ser,NP, 0.719; Met,NP, 0.719; KynA,NP, 0.717; Arg,Lys, 0.71; Ala,Arg, 0.71; Ala,Kyn, 0.71; His,AnthA, 0.71; Pro,NP, 0.706; Trp,KynA, 0.705; AnthA,KynA, 0.702; His,hKyn, 0.7; AnthA,QA, 0.698; hKyn,AnthA, 0.697; Gln,NP, 0.695; AnthA,Kyn, 0.694; Thr,KynA, 0.692; Asn,NP, 0.692; Ser,AnthA, 0.689; Pro,hKyn, 0.687; Ala,AnthA, 0.683; Ala,KynA, 0.679; Trp,Kyn, 0.678; Trp,hKyn, 0.678; Ala,NP, 0.678; Thr,hKyn, 0.676; Gly,NP, 0.675; Ala, hKyn, 0.675; Lys,hKyn, 0.67; hKyn,hTrp, 0.665; Lys,NP, 0.665; Thr,AnthA, 0.663; hTrp,QA, 0.663; Trp,AnthA, 0.663; hKyn,KynA, 0.663; Lys,AnthA, 0.662; No, QA, 0.662; Pro,Kyn, 0.66; Thr,QA, 0.657; Asn,Kyn, 0.656; Ser,hKyn, 0.654; Pro,AnthA, 0.652; hKyn,QA, 0.652; Met,hKyn, 0.652; Asn,hKyn, 0.651; Gln,QA, Asn,QA, 0.648; Lys,QA, 0.643; hKyn,Kyn, 0.641; Lys,KynA, 0.637; Ala,Met, 0.632; Asn,AnthA, 0.632; KynA,QA, 0.629; Gly,Trp, 0.627; Gly,Ala, 0.624; Pro,KynA, 0.622; Gly,hKyn, 0.622; Gly,Lys, 0.621; Ala,hTrp, 0.621; Met,KynA, 0.619; Gln,Ala, 0.619; His,Ala, 0.617; Gly,QA, 0.617; Met,Kyn, 0.614; Thr,Ala, 0.613; Gly,AnthA, 0.613; Ala,Trp, 0.606; 0.592; Gln,hKyn, 0.587.

[0189] [307. A three-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index] Arg,Met,NP, 0.825; Thr,Arg,QA, 0.797; Arg,QA,NP, 0.792; Arg,Trp,NP, 0.79; Arg,hTrp,NP, 0.789; Arg,Met,Kyn, 0.787; Arg,KynA,QA, 0.784; Arg,Kyn,NP, 0.784; Arg,Lys,NP, 0.783; Ser,Arg,NP, 0.783; Arg,hKyn,NP, 0.783; Gln,Arg,NP, 0.781; His,Arg,NP, 0.781; Asn,Arg,QA, 0.778; Arg,Pro,NP, 0.778; Ser,Arg,QA, 0.773; His,Arg,QA, 0.771; Arg,AnthA,Kyn, 0.771; Trp,AnthA,KynA, 0.771; Arg,hTrp,QA, 0.77; Gln,Arg,QA, 0.767; Arg,KynA,KynA, 0.767; His,KynA,NP, 0.767; Arg,Lys,QA, 0.765; Arg,hTrp,Kyn, 0.763; Gly,Arg,QA, 0.763; Arg,HKyn,KynA, 0.763; Arg,hKyn,AnthA, 0.763; Ala,Arg,Kyn, 0.76; Ala,Arg,QA, 0.756; AnthA,KynA,NP, 0.756; Ala,Arg,NP, 0.749; Pro,hKyn,AnthA, 0.749; Arg,hKyn,hTrp, 0.746; Ala,KynA,NP, 0.746; Gly,Arg,hKyn, 0.744; Pro,hKyn,NP, 0.741; hKyn,AnthA,NP, 0.74; Thr,Arg,HKyn, 0.737; Ser,Arg,hKyn, 0.733; Arg,Trp,hKyn, 0.732; Ala,Kyn,NP, 0.73; Arg,Pro,hKyn, 0.729; His,hKyn,AnthA, 0.729; Arg,Lys,hKyn, 0.727; Ala,AnthA,QA, 0.724; Ala,AnthA,Kyn, 0.724; Trp,hKyn,AnthA, 0.724; Ala, Arg, HKyn, 0.722; Ala,hKyn,AnthA, 0.722; hKyn,AnthA,KynA, 0.719; Ala,KynA,Kyn, 0.719; Ala,hTrp,Kyn, 0.717; Lys,hKyn,AnthA, 0.716; Trp,hKyn,KynA, 0.713; Gly,Ala,Kyn, 0.71; Thr,hKyn,AnthA, 0.71; Ala, Kyn, QA, 0.708; Ala,hKyn,Kyn, 0.708; Ala,Trp,Kyn, 0.703; Ala,Lys,Kyn, 0.703; Ala,Met,Kyn, 0.703; Ser,Ala,Kyn, 0.702; Met,hKyn,AnthA, 0.698; Gly,Ala,NP, 0.697; Asn,hKyn,AnthA, 0.697; Ala,hKyn,KynA, 0.697; Ala,hTrp,NP, 0.695; Pro,Lys,hKyn, 0.689; Thr,Ala,KynA, 0.687; Gly,Lys,hKyn, 0.687; Ala, KynA, QA, 0.687; Asn,Ala,KynA, 0.686; Gly,Ala,KynA, 0.686; Lys,hKyn,KynA, 0.686; Lys,hKyn,NP, 0.686; Ala,hKyn,hTrp, 0.684; Ala,Lys,KynA, 0.683; Ala, hKyn, QA, 0.683; Gln,Ala,KynA, 0.683; His,Ala,KynA, 0.683; Ala,Met,KynA, 0.678; Ser,Ala,hKyn, 0.678; Lys,hKyn,hTrp, 0.678; Gly,Trp,hKyn, 0.676; Ala,Trp,hKyn, 0.676; Ala,Pro,hKyn, 0.676; Ala,Pro,KynA, 0.675; Ala,Met,hKyn, 0.675; Ser,Ala,KynA, 0.673; Gly,hKyn,AnthA, 0.673; Thr,Lys,hKyn, 0.671; Ala,Lys,hKyn, 0.671; Lys,hKyn,QA, 0.67; His,Ala,hKyn, 0.668; Gln, Ala, hKyn, 0.667; Gly,Ala,QA, 0.665; Gly,Ala,hKyn, 0.665; Gln,Lys,hKyn, 0.656; Gln,hKyn,AnthA, 0.646.

[0190] [308. A four-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index] Ser,Arg,KynA,NP, 0.827; Arg,Pro,Met,NP, 0.825; Arg,Met,Trp,NP, 0.824; Arg,AnthA,KynA,NP, 0.822; Gly,Arg,Met,NP, 0.816; His,Arg,Met,NP, 0.814; Arg,Lys,KynA,NP, 0.813; Thr,Arg,KynA,NP, 0.81; Arg, AnthA, KynA, QA, 0.806; Arg,Met,AnthA,QA, 0.805; Arg,Met,Lys,NP, 0.803; Arg,hTrp,KynA,QA, 0.795; Arg,AnthA,KynA,KynA, 0.79; Arg,hKyn,hTrp,NP, 0.781; Gly,Thr,Arg,QA, 0.779; Ala,AnthA,KynA,NP, 0.779; His,hKyn,AnthA,KynA, 0.775; Ala, Arg, AnthA, KynA, 0.775; Arg,Trp,hKyn,QA, 0.771; Arg,hKyn,hTrp,QA, 0.771; Ala,Arg,Kyn,NP, 0.771; Pro,hKyn,AnthA,KynA, 0.771; Thr,Arg,hKyn,AnthA, 0.768; Thr,Ala,Arg,Kyn, 0.767; Asn,Arg,HKyn,QA, 0.765; Arg,Pro,hKyn,NP, 0.765; Ser,Arg,hKyn,AnthA, 0.765; Ala,Arg,KynA,Kyn, 0.763; Ala,Arg,AnthA,NP, 0.763; Ala, Arg, Kyn, QA, 0.762; Ser,Ala,Arg,Kyn, 0.76; Gly,Ala,KynA,NP, 0.76; Arg,Lys,hKyn,NP, 0.759; Ala,hTrp, AnthA, KynA, 0.759; Ala,Arg,Lys,KynA, 0.757; Ala,Arg,Met,Lys, 0.756; Asn,Ala,Arg,KynA, 0.756; Ala,Arg,Lys,Kyn, 0.754; Ala,Arg,hKyn,AnthA, 0.754; Ser, Ala, AnthA, KynA, 0.754; Ala, Trp, AnthA, KynA, 0.754; Arg,Met,Light,hKyne, 0.752; Ala,Arg,Met,hKyne, 0.752; Pro,hKyn,KynA,NP, 0.751; His, Ala, AnthA, KynA, 0.751; Gly,Ala,AnthA,KynA, 0.751; Ala,Arg,hKyn,KynA, 0.748; Ala,hTrp,KynA,NP, 0.748; Ala,AnthA,KynA,Kyn, 0.748; Ala, hKyn, AnthA, KynA, 0.748; Ala,Trp,KynA,NP, 0.743; Gln,Ala,KynA,NP, 0.741; Ser,Ala,KynA,NP, 0.741; His,Pro,hKyn,AnthA, 0.74; Ala,Met,AnthA,NP, 0.738; Pro,Trp,hKyn,AnthA, 0.738; Ala, Met, AnthA, KynA, 0.737; Thr,Ala,Arg,hKyn, 0.735; Arg,Lys,hKyne,hTrp, 0.733; Ala, Trp, AnthA, Kyn, 0.732; Gly,Ala,KynA,Kyn, 0.732; Thr,Ala,AnthA,Kyn, 0.73; Ala, hKyn, AnthA, QA, 0.73; Ala, hKyn, hTrp, AnthA, 0.73; Trp, hKyn, hTrp, AnthA, 0.729; Thr,Ala,hKyn,AnthA, 0.725; Gln,Ala,AnthA,Kyn, 0.724; Gly, Ala, AnthA, Kyn, 0.724; Trp,hKyn,AnthA,Kyn, 0.724; Lys, hKyn, AnthA, NP, 0.724; Gln,Ala,Arg,hKyn, 0.722; Ala,Lys,KynA,Kyn, 0.722; Ala, Lys, hKyn, AnthA, 0.722; Ala, hTrp, Kyn, QA, 0.721; His, Ala, AnthA, Kyn, 0.721; Ala,Trp,KynA,Kyn, 0.719; Ala,KynA,Kyn,QA, 0.719; His,Lys,hKyn,AnthA,717; Lys,hKyn,AnthA,QA, 0.717; Gly,Ala,hKyn,AnthA, 0.717; Ala,Lys,hTrp,Kyn, 0.716; Asn,Ala,KynA,Kyn, 0.716; Thr,Lys,hKyn,AnthA, 0.716; Ala,Lys,hKyn,Kyn, 0.714; Ala,Met,KynA,Kyn, 0.714; Asn,Gly,Ala,Kyn, 0.708; Gly,Ala,KynA,QA, 0.708; Ala,hKyn,KynA,QA, 0.708; Gly,Ala,Met,Kyn, 0.702; Asn,Ala,hKyn,KynA, 0.702; Ala,Pro,hKyn,KynA, 0.697; Thr,Ala,hKyn,KynA, 0.697; Thr,Ala,KynA,QA, 0.694; Gly,Ala,hTrp,KynA, 0.694; Ala,Met,hKyn,KynA, 0.694; Thr,Ala,Met,hKyn, 0.687; Gln,Ala,hTrp,KynA, 0.687; Ala,Trp,KynA,QA, 0.687; Ala,Met,KynA,QA, 0.687; Gly,Ala,Lys,hKyn, 0.675.

[0191] [309. A five-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index] Arg,Pro,HKyn,AnthA,KynA, 0.808; Arg,hKyn,AnthA,KynA,NP, 0.805; Asn,Ala,Arg,Met,NP, 0.805; Ala,Arg,Met,Trp,NP, 0.803; Arg,Pro,Met,hKyn,NP, 0.802; Ala,Arg,Met,AnthA,Kyn, 0.797; Ala,Arg,Met,Trp,Kyn, 0.794; Thr,Ala,Arg,KynA,NP, 0.794; Thr,Ala,Arg,AnthA,KynA, 0.792; His,Ala,Arg,Met,Kyn, 0.789; Gln,Ala,Arg,KynA,NP, 0.789; Gly,Ala,AnthA,KynA,NP, 0.781; Gly,Ala,Arg,Met,Kyn, 0.781; Ala,Arg,Met,Trp,KynA, 0.781; Ala,Arg,AnthA,Kyn,NP, 0.781; Ala,Arg,Met,hKyn,NP, 0.779; Gly,Arg,hKyn,AnthA,NP, 0.779; Arg,HKyn,AnthA,Kyn,QA, 0.779; Thr,Ala,Arg,KynA,QA, 0.778; Ala,Arg,Met,Lys,KynA, 0.778; Asn,Arg,hKyn,AnthA,QA, 0.778; Ala, Arg, Met, hTrp, KynA, 0.776; Asn,Ala,Arg,AnthA,KynA, 0.775; Arg,Met,Lys,hKyn,AnthA, 0.775; Asn,Trp,hKyn,AnthA,KynA, 0.775; Ala,Arg,Pro,KynA,NP, 0.775; Ala,Arg,Trp,Kyn,NP, 0.775; Asn,Ala,Arg,KynA,KynA, 0.773; Ala, Lys, hTrp, AnthA, KynA, 0.768; Arg,Lys,HKyn,AnthA,Kyn, 0.768; His,hKyn,AnthA,KynA,NP, 0.768; Ala,hKyn,AnthA,KynA,NP, 0.767; Ala,Arg,HKyn,AnthA,KynA, 0.767; Ala, hTrp, AnthA, KynA, QA, 0.763; Ala,Arg,hTrp,KynA,Kyn, 0.763; Ala,hKyn,hTrp,AnthA,KynA, 0.762; Ser,Trp,HKynA,AnthA,KynA, 0.762; Ala,Arg,Met,Trp,hKyn, 0.762; Ala,Met,AnthA,KynA,NP, 0.76; Thr,Ala,hTrp,AnthA,KynA, 0.759; Ala, Arg, hKyn, KynA, QA, 0.759; Ala, Arg, Met, hKyn, hTrp, 0.759; Ala,Arg,hKyn,hTrp,AnthA, 0.757; Ala,hTrp,AnthA,KynA,Kyn, 0.756; Asn,Ala,Arg,HKyn,KynA, 0.756; Gln,Ala,KynA,Kyn,NP, 0.756; Arg,Pro,Lys,hKyn,AnthA, 0.756; Thr,Ala,Arg,hKyn,NP, 0.754; Ala, Trp, AnthA, KynA, QA, 0.752; Ala, hKyn, AnthA, KynA, QA, 0.751; Ser,Gln,Ala,AnthA,KynA, 0.751; Gln,Thr,Ala,KynA,NP, 0.751; Gly,Arg,Lys,hKyn,AnthA, 0.749; Ala,hKyn,AnthA,KynA,Kyn, 0.748; Gly,Ala,AnthA,KynA,Kyn, 0.748; Ser,Pro,Lys,hKyn,AnthA, 0.748; Gly,Pro,hKyn,AnthA,NP, 0.748; Gly,Ala,Arg,Kyn,QA, 0.748; Ala,Pro,AnthA,KynA,Kyn, 0.744; His,Ala,Met,KynA,Kyn, 0.743; Gly,Ala,hTrp,Kyn,NP, 0.743; Gly,Ala,Arg,HKyn,QA, 0.743; Asn,Arg,Met,Lys,HKyn, 0.743; His,Ala,hKyn,AnthA,NP, 0.741; Ala,hKyn,hTrp,AnthA,QA, 0.738; Ala,Met,hTrp,KynA,NP, 0.735; Ser,Ala,AnthA,KynA,Kyn,0.733; Gly,Ala,hTrp,KynA,KynA, 0.733; Ala,Met,hKyn,KynA,NP, 0.733; Gln,Ala,hTrp,AnthA,Kyn, 0.733; His,Ala,hTrp,AnthA,Kyn, 0.733; Ser,Ala,Lys,HKyn,AnthA, 0.733; Thr,Ala,hTrp,KynA,KynA, 0.729; Ser,Gln,Ala,HKyn,AnthA, 0.729; Ala, Met, hKyn, hTrp, AnthA, 0.727; Ala,Lys,Trp,HKyn,AnthA, 0.727; Gly,Ala,Pro,KynA,Kyn, 0.725; Gly,Ala,hKyn,AnthA,QA, 0.725; Gln,Ala,HKyn,AnthA,QA, 0.725; Thr,Ala,Lys,hKyn,AnthA, 0.724; His,Thr,Ala,KynA,Kyn, 0.722; Asn,Thr,Ala,KynA,KynA, 0.721; Thr,Ala,Pro,KynA,KynA, 0.721; Gln,Ala,Lys,HKyn,AnthA, 0.721; Gln,Ala,Pro,KynA,Kyn, 0.719; Gln,Ala,Met,KynA,NP, 0.719; Ser,Gly,Ala,hKyn,AnthA, 0.716; Ser,Ala,hTrp,KynA,Kyn, 0.713; Ser,Thr,Ala,hKyn,KynA, 0.71; Ala, Met, Lys, hKyn, AnthA, 0.706; Ala, Pro, hKyn, KynA, QA, 0.705; His,Ala,Met,hKyn,KynA, 0.703; Thr,Ala,HKN,HTrp,KYNA, 0.702; Asn,His,Ala,hKyn,KynA, 0.702; His,Ala,Trp,HKyn,KynA, 0.702; Asn, Ala, hTrp, KynA, QA, 0.702; Ser,Ala,HKyn,KynA,QA, 0.7; Ala, Met, hTrp, KynA, QA, 0.7; Ser,Ala,Trp,HKyn,KynA, 0.698; Gly,Ala,Met,hKyn,KynA, 0.697.

[0192] [310. A six-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment with PFS as an evaluation index] Ala, Arg, Met, KynA, QA, NP, 0.814; Asn,Ala,Arg,Lys,KynA,NP, 0.808; Ala,Arg,Pro,Met,Lys,NP, 0.802; Ala, Arg, Met, Lys, KynA, QA, 0.798; Ser,His,Ala,Arg,KynA,NP, 0.798; Gly,Ala,hTrp,AnthA,KynA,NP, 0.797; Ala, Arg, Met, hTrp, Kyn, QA, 0.795; Ala,Arg,Met,Lys,Trp,NP, 0.795; His,Ala,Arg,KynA,Kyn,NP, 0.794; Ala,Arg,Met,Trp,AnthA,QA, 0.794; Thr,Ala,Met,AnthA,KynA,NP, 0.792; Ser,Gly,Ala,Arg,Met,Kyn, 0.784; His,Ala,Arg,Met,hKyn,Kyn, 0.784; Ser,Asn,Ala,Arg,AnthA,Kyn, 0.784; Ala, Arg, Met, hKyn, KynA, QA, 0.783; Pro,Lys,hKyn,AnthA,KynA,Kyn, 0.781; Pro,hKyn,AnthA,KynA,Kyn,NP, 0.781; Arg,Trp,HKyn,HTrp,AnthA,KynA, 0.781; Asn,Gly,Ala,Arg,AnthA,Kyn, 0.781; Asn,Gly,Ala,AnthA,KynA,NP, 0.779; Ser,Arg,Trp,HKyn,AnthA,KynA, 0.779; Asn, Ala, Arg, hTrp, AnthA, KynA, 0.778; His,Ala,Arg,hKyn,AnthA,Kyn, 0.778; Asn,Arg,Trp,HKyn,AnthA,KynA, 0.778; Gly,Ala,Arg,Met,hTrp,KynA, 0.778; Ala,Lys,hKyn,AnthA,KynA,NP, 0.776; Gln,Ala,Lys,AnthA,KynA,NP, 0.776; Ala, Pro, hTrp, AnthA, KynA, QA, 0.776; Asn,Ala,Trp,AnthA,KynA,KynA,0.775; Asn,Ala,Trp,HKyn,AnthA,KynA, 0.775; Ala, Arg, Pro, hTrp, AnthA, KynA, 0.775; Ser,Asn,Ala,Arg,AnthA,KynA, 0.775; Thr,Arg,Lys,HKyn,AnthA,KynA, 0.775; Thr,Ala,Arg,Pro,Met,KynA, 0.775; Ala,Arg,Met,Lys,hKyn,NP, 0.771; His,Ala,Pro,AnthA,KynA,QA, 0.771; His,Ala,Arg,Lys,KynA,Kyn, 0.771; Pro,hTrp,AnthA,KynA,QA,NP, 0.771; Gln,Pro,HKyn,AnthA,KynA,QA, 0.77; Asn,Gly,Ala,Trp,AnthA,KynA, 0.765; Asn,Ala,Arg,HKyn,HTRP,AnthA, 0.765; Ala,Arg,Lys,hKyn,AnthA,Kyn, 0.765; Gln,Ala,Arg,HKN,KynA,Kyn, 0.763; Ser,Asn,Ala,AnthA,KynA,QA, 0.763; Asn,Gly,Ala,hTrp,AnthA,KynA, 0.763; Gly,Arg,Pro,Met,Lys,hKyn, 0.763; Gln,Ala,hTrp,KynA,Kyn,NP, 0.762; Gly, Ala, Lys, AnthA, KynA, QA, 0.762; Gly,Gln,Trp,HKyn,AnthA,KynA, 0.762; Gly,Ala,Arg,hKyn,AnthA,NP, 0.762; Ala,Lys,hKyn,hTrp,AnthA,KynA, 0.76; Ala,Arg,Trp,hKyn,AnthA,NP, 0.76; Ala,hTrp, AnthA, KynA, Kyn, QA, 0.759; Asn,Ala,hKyn,hTrp,AnthA,KynA, 0.759; Pro,Met,Lys,hKyn,hTrp,AnthA, 0.759; Asn,Gly,Thr,Ala,KynA,NP, 0.759; Thr,Ala,Arg,Pro,HKyn,AnthA,0.759; Ser,Thr,Trp,HKyn,AnthA,KynA, 0.757; Gly,Ala,hTrp,AnthA,KynA,Kyn, 0.756; Asn,Ala,hTrp,AnthA,KynA,Kyn, 0.754; Gly,Thr,Ala,Arg,HKyn,AnthA, 0.754; Ala, Met, Lys, AnthA, KynA, QA, 0.752; Ser,Ala,hKyn,hTrp,AnthA,KynA, 0.749; Asn,Ala,AnthA,KynA,Kyn,QA, 0.749; Gly,Ala,Trp,HKyn,AnthA,KynA, 0.749; Thr,Ala,hTrp,AnthA,KynA,Kyn, 0.748; Thr,Ala,HKN,AnthA,CyneA, 0.748; Ala,Pro,AnthA,KynA,Kyn,QA, 0.748; Ala,Pro,Lys,AnthA,KynA,Kyn, 0.746; Gly,Thr,Ala,AnthA,KynA,Kyn, 0.746; Ser,Gln,Ala,hTrp,KynA,NP, 0.746; Asn,Gln,Ala,hTrp,KynA,NP, 0.746; Ala,Trp,hKyn,KynA,Kyn,NP, 0.744; Ser,Gly,Ala,hTrp,KynA,NP, 0.743; Asn,Gln,Ala,KynA,Kyn,NP, 0.743; Ser, Ala, hTrp, AnthA, KynA, Kyn, 0.741; Asn,Ala,hKyn,AnthA,KynA,Kyn, 0.741; Gly,Gln,Ala,hKyn,AnthA,KynA, 0.741; His,Ala,Met,hTrp,KynA,Kyn, 0.741; Gln,His,Ala,Met,KynA,Kyn, 0.741; Gln,His,Ala,AnthA,KynA,Kyn, 0.74; His,Ala,hKyn,hTrp,KynA,Kyn, 0.74; Gln,Ala,Pro,hTrp,KynA,Kyn, 0.74; Ala, Met, hTrp, AnthA, KynA, Kyn, 0.738; Ser,Thr,Ala,AnthA,KynA,Kyn,0.737; Gly,Ala,hKyn,hTrp,AnthA,Kyn, 0.737; Gly,Ala,Met,KynA,QA,NP, 0.737; Ser,Gly,Ala,Trp,KynA,NP, 0.735; Gly,His,Ala,hTrp,KynA,Kyn, 0.733; Asn,Ala,Lys,hTrp,KynA,Kyn, 0.729; Asn,Thr,Ala,hKyn,KynA,Kyn, 0.727; Thr,Ala,Met,hKyn,AnthA,Kyn, 0.727; Asn,Ala,Trp,hTrp,KynA,Kyn, 0.725; Asn,Gln,Ala,hTrp,KynA,Kyn, 0.724; Ala,Met,hKyn,hTrp,KynA,Kyn, 0.724; Asn,Thr,Ala,KynA,Kyn,QA, 0.724; Gly,Thr,Ala,Met,KynA,Kyn, 0.719; Asn,Gly,Ala,hKyn,AnthA,QA, 0.716; His,Ala,Met,hKyn,hTrp,KynA, 0.711; Gly,Gln,Ala,hKyn,hTrp,KynA, 0.705.

[0193] [311. Two-variable formula obtained from amino acids before the start of treatment using response rate as an evaluation index] Arg,Met, 0.691; Ala,Phe, 0.686; Gly,Arg, 0.681; Ala,Orn, 0.676; Ser,Arg, 0.672; Thr,Arg, 0.671; Gln,Arg, 0.666; Ala,Arg, 0.666; Ala,Met, 0.664; Asn,Ala, 0.66; Arg,Orn, 0.652; Ala,Lys, 0.652; Arg,Ile, 0.65; His,Arg, 0.65; Ala,Cit, 0.65; Gly,Orn, 0.649; Ala,Ile, 0.647; His,Ala, 0.647; Arg,Val, 0.645; Arg,Pro, 0.642; Arg,Tyr, 0.642; Ala,Val, 0.642; Thr,Ala, 0.642; Ala,Pro, 0.64; Arg,Phe, 0.64; Arg,Lys, 0.639; Tyr,Orn, 0.639; Ala,Leu, 0.639; Ala,Tyr, 0.639; Gln,Ala, 0.637; Met,Orn, 0.635; Pro,Orn, 0.633; Cit,Arg, 0.633; Ala,Trp, 0.633; Ser,Ala, 0.633; Ser,Orn, 0.632; Cit,Orn, 0.63; Gln,Orn, 0.628; Asn,Orn, 0.627; Orn,Phe, 0.627; Lys,Phe, 0.625; Orn,Lys, 0.623; Gly,Ala, 0.623; Val,Phe, 0.62; Pro,Phe, 0.62; Orn,Trp, 0.618; Val,Orn, 0.615; Met,Trp, 0.615; Phe,Trp, 0.615; Orn,Leu, 0.611; His,Orn, 0.611; Thr,Orn, 0.611; Cit,Phe, 0.61; Orn,Ile, 0.606; Thr,Phe, 0.606; Cit,Pro, 0.606; Gly,Cit, 0.605; Tyr,Trp, 0.6; Tyr,Phe, 0.596; Thr,Lys, 0.595; Asn,Cit, 0.591; Gly,Trp, 0.588; Cit,Tyr, 0.586; Thr,Cit, 0.586; Cit,Trp, 0.586; Gly,Lys, 0.584; Met,Lys, 0.584; Pro,Trp, 0.584; Ser,Lys, 0.581; Ile,Trp, 0.581; Thr,Pro, 0.579; Leu,Phe, 0.579; Asn,Lys, 0.574; Val,Lys, 0.574; Val,Trp, 0.574; Gln,Trp, 0.573; Cit,Ile, 0.571; Gln,Lys, 0.571; His,Trp, 0.571; Lys,Trp, 0.571; Leu, Trp, 0.571; Tyr,Lys, 0.569; His,Lys, 0.569; Lys,Leu, 0.569; Lys,Ile, 0.569; Thr,Trp, 0.566; Gly,Thr, 0.564.

[0194] [312. Three-variable formula derived from amino acids before the start of treatment using response rate as an evaluation index] Ala,Orn,Phe, 0.743; Ala,Arg,Met, 0.738; Ser,Arg,Met, 0.715; Gly,Arg,Pro, 0.709; Gly,Arg,Leu, 0.708; Gly,Arg,Ile, 0.708; Asn,Ala,Cit, 0.708; Arg,Val,Met, 0.708; Ala,Cit,Met, 0.708; Ala,Arg,Phe, 0.704; Arg,Pro,Met, 0.703; Asn,Ala,Orn, 0.701; Gly,Thr,Arg, 0.699; Ala,Leu,Phe, 0.696; Pro,Orn,Phe, 0.694; Arg,Met,Orn, 0.693; Ala,Met,Phe, 0.693; Ala, Val, Orn, 0.693; Arg, Tyr, Met, 0.691; Asn, Ala, Arg, 0.689; Gly, His, Arg, 0.688; Gln, Arg, Phe, 0.688; Ser,Ala,Phe, 0.688; Thr,Arg,Trp, 0.686; Gly, Arg, Orn, 0.686; Ala, Lys, Phe, 0.686; Ala, Orn, Ile, 0.686; Thr,Ala,Orn, 0.686; Gly, Gln, Arg, 0.684; Ala, Val, Phe, 0.684; His, Ala, Arg, 0.682; Ala,Phe,Trp, 0.682; Gln, Arg, Pro, 0.681; Ser,Arg,Ile, 0.681; Ala,Arg,Val, 0.681; Thr,Ala,Phe, 0.681; Ala,Tyr,Phe, 0.679; Ser,Ala,Arg, 0.679; Ser,Arg,Pro, 0.677; Ala,Cit,Orn, 0.677; Ala,Ile,Phe, 0.677; Ala,Cit,Lys, 0.674; Ala,Pro,Orn, 0.674; Ala,Pro,Phe, 0.674; Gln,Ala,Phe, 0.674; Ser,Asn,Arg, 0.672; His,Ala,Orn, 0.672; Asn,Ala,Met, 0.671; Ala,Arg,Leu, 0.669; Ser,Cit,Arg, 0.667; Ala,Cyt,Arg, 0.667; Val,Orn,Phe, 0.666; Gly,Ala,Arg, 0.666; Ala,Arg,Pro, 0.664; Gln, Ala, Cyt, 0.664; Gly, Phe, Trp, 0.662; Ala,Arg,Trp, 0.662; Ala,Tyr,Met, 0.662; Gln, Ala, Met, 0.662; Asn, Gln, Arg, 0.66; Ala,Cit,Ile, 0.66; Ala,Tyr,Trp, 0.659; His, Ala, Cyt, 0.659; Asn, Arg, Phe, 0.657; Ser,Ala,Met, 0.657; Arg, Val, Phe, 0.657; Serum, Asn, Ala, 0.655; Tyr,Orn,Phe, 0.654; Asn,Arg,Trp, 0.654; His,Thr,Ala, 0.654; Ala,Cit,Val, 0.654; Asn,Ala,Leu, 0.654; Ala,Cit,Leu, 0.652; Asn,Ala,Trp, 0.65; Pro,Val,Phe, 0.649; Arg,Pro,Tyr, 0.649; Arg,Lys,Phe, 0.649; Arg,Ile,Phe, 0.647; Asn,Gln,Ala, 0.647; Ala,Leu,Trp, 0.642; Ala,Lys,Trp, 0.642; His,Ala,Leu, 0.64; His,Ala,Tyr, 0.64; Gln,Ala,Ile, 0.639; Ser,Ala,Val, 0.639; Cyt,Arg,Phe, 0.639; Ser,Ala,Lys, 0.637; Gly,Ala,Leu, 0.633; His,Phe,Trp, 0.632; Val,Phe,Trp, 0.632; Gln,Ala,Lys, 0.632; Ser,His,Ala, 0.63; Ser,Ala,Trp, 0.627; Gln,Ala,Pro, 0.627; Asn,Gly,Ala, 0.627; Gly,Ala,Val, 0.625; His,Ala,Trp, 0.623; Ala,Tyr,Leu, 0.623.

[0195] [313. A four-variable formula derived from amino acids before the start of treatment using response rate as an evaluation index] Ser,Ala,Orn,Phe, 0.794; Gln,Ala,Orn,Phe, 0.789; Ala,Arg,Met,Leu, 0.765; Gly,Arg,Pro,Met, 0.76; Thr,Ala,Orn,Phe, 0.758; Ala,Orn,Lys,Phe, 0.755; Ala,Pro,Orn,Phe, 0.753; His,Ala,Arg,Met, 0.748; Ala,Arg,Pro,Met, 0.748; Ala,Orn,Ile,Phe, 0.747; Ala,Arg,Met,Ile, 0.745; Ala,Arg,Orn,Phe, 0.743; Ala,Ile,Leu,Phe, 0.738; Thr,Ala,Arg,Met, 0.736; Ala,Arg,Met,Phe, 0.735; Gly,Ala,Arg,Phe, 0.735; Ala,Met,Orn,Leu, 0.733; Ala,Pro,Met,Orn, 0.733; Asn,Ala,Arg,Met, 0.731; Thr,Ala,Met,Orn, 0.73; Ala,Met,Orn,Trp, 0.728; Arg,Met,Leu,Phe, 0.726; Asn,Ala,Arg,Phe, 0.726; Arg,Pro,Met,Leu, 0.726; Ala,Arg,Tyr,Orn, 0.723; Asn,Ala,Cit,Phe, 0.723; Pro,Val,Orn,Phe, 0.718; Thr,Ala,Cit,Met, 0.718; His,Arg,Met,Trp, 0.718; Ser,Arg,Met,Phe, 0.716; Arg,Pro,Val,Met, 0.716; Gln, Ala, Arg, Tyr, 0.715; Gln, Arg, Met, Trp, 0.715; His, Ala, Met, Orn, 0.713; Ala,Tyr,Orn,Ile, 0.711; Arg, Met, Orn, Trp, 0.711; Ala,Cit,Val,Met, 0.711; Asn, Gly, Ala, Arg, 0.711; Asn, Gly, Ala, Orn, 0.711; Ala,Cit,Met,Ile, 0.711; Gly, Arg, Orn, Phe, 0.711; Thr, Arg, Met, Trp, 0.709; Ala,Cit,Met,Leu, 0.709; Ala,Arg,Leu,Phe, 0.708; Gly,Ala,Arg,Lys, 0.708; Ser,Ala,Met,Orn, 0.708; Ala,Arg,Phe,Trp, 0.704; Cit,Arg,Pro,Met, 0.704; Asn,Ala,Val,Phe, 0.704; Ala,Cit,Tyr,Met, 0.703; Ala,Cit,Pro,Met, 0.703; Gln,Ala,Orn,Ile, 0.703; Ala,Val,Lys,Phe, 0.701; Arg,Pro,Tyr,Met, 0.701; Asn,Ala,Orn,Trp, 0.701; His,Ala,Tyr,Orn, 0.701; Gly,Ala,Cit,Met, 0.701; Gln,Ala,Orn,Lys, 0.701; Thr,Arg,Val,Phe, 0.699; Ser,Cit,Arg,Phe, 0.699; Ala,Val,Met,Phe, 0.699; Ala,Tyr,Orn,Lys, 0.699; Asn,Ala,Cit,Orn, 0.699; Asn,Ala,Orn,Leu, 0.699; Gln,Arg,Pro,Met, 0.699; Gln,His,Ala,Orn, 0.699; Asn,Ala,Orn,Ile, 0.698; Gly,Cit,Arg,Phe, 0.698; Gln,Ala,Pro,Orn, 0.696; Ser,Ala,Cit,Phe, 0.696; Ser, His, Ala, Orn, 0.694; Ala,Leu,Phe,Trp, 0.693; Gly, Thr, Arg, Phe, 0.693; Gly, Arg, Ile, Phe, 0.693; Gly, Arg, Leu, Phe, 0.693; Ser, Gln, Arg, Phe, 0.691; Gly,Ala,Leu,Phe, 0.691; Ala, Cyt, Lys, Phe, 0.689; Ala, Cyt, Tyr, Phe, 0.688; Gln, Arg, Orn, Phe, 0.688; Ser,Ala,Arg,Orn, 0.688; Ser,Ala,Val,Orn, 0.686; Gly, Ala, Tyr, Orn, 0.686; His,Ala,Val,Orn, 0.682; Gly,Thr,Ala,Orn, 0.681; Ala,Cit,Ile,Phe, 0.679; Gly,Ala,Orn,Leu, 0.679; Ser,Ala,Orn,Ile, 0.677; Ser,Ala,Phe,Trp, 0.677; Ala,Met,Leu,Trp, 0.676; Ser,Arg,Pro,Phe, 0.676; Ser,Ala,Tyr,Orn, 0.672; Gln,Ala,Leu,Phe, 0.671; Ala,Met,Lys,Trp, 0.669; Ser,Ala,Orn,Trp, 0.669; Gln,Ala,Met,Trp, 0.667; His,Ala,Met,Trp, 0.667; Arg,Orn,Phe,Trp, 0.662; Ser,Ala,Pro,Orn, 0.657; Thr,Ala,Met,Trp, 0.655.

[0196] [314. A five-variable formula derived from amino acids before the start of treatment using response rate as an evaluation index] Ala,Met,Orn,Leu,Phe, 0.813; Gly, Ala, Orn, Phe, Trp, 0.802; Gly, Thr, Ala, Orn, Phe, 0.802; Gly, Ala, Orn, Ile, Phe, 0.799; Gly, His, Ala, Orn, Phe, 0.799; Gly, Ala, Cyt, Orn, Phe, 0.797; Gly, Ala, Orn, Leu, Phe, 0.797; Gln, Ala, Pro, Orn, Phe, 0.796; Gly, Gln, Ala, Orn, Phe, 0.796; Ser, Ala, Orn, Lys, Phe, 0.794; Gly, Ala, Orn, Lys, Phe, 0.794; Gly, Ala, Arg, Orn, Phe, 0.791; Asn,Ala,Orn,Phe,Trp, 0.784; Ala,Orn,Ile,Leu,Phe, 0.784; His,Ala,Pro,Orn,Phe, 0.78; Gln,Ala,Arg,Orn,Phe, 0.78; His,Ala,Cit,Orn,Phe, 0.779; Ser,Ala,Arg,Orn,Phe, 0.779; His,Ala,Orn,Lys,Phe, 0.774; Asn,Ala,Arg,Met,Leu, 0.77; Asn,Ala,Orn,Lys,Phe, 0.77; His,Ala,Arg,Met,Leu, 0.767; Ala,Cit,Orn,Leu,Phe, 0.764; Ala,Arg,Orn,Leu,Phe, 0.758; Gly,Cit,Arg,Pro,Met, 0.753; Thr,Ala,Arg,Met,Orn, 0.752; Asn,Ala,Cit,Leu,Phe, 0.75; Ala,Pro,Orn,Ile,Phe, 0.747; Ala,Arg,Met,Ile,Phe, 0.747; Gly,His,Ala,Arg,Phe, 0.745; Thr,Ala,Met,Orn,Leu, 0.743; Ala,Arg,Val,Met,Phe, 0.743; Gly,Ala,Arg,Ile,Phe, 0.742; Ala,Met,Ile,Leu,Phe, 0.74; Asn,Ala,Arg,Met,Lys, 0.738; Ala,Cit,Val,Met,Phe, 0.738; Asn,Ala,Arg,Met,Trp, 0.738; Gln,Ala,Arg,Met,Trp, 0.738; Ser,Asn,Ala,Arg,Met, 0.738; Gln,Ala,Ile,Leu,Phe, 0.736; Ala,Met,Orn,Lys,Leu, 0.736; Ala,Pro,Met,Leu,Phe, 0.735; His,Thr,Ala,Met,Orn, 0.733; Gln,Ala,Arg,Met,Phe, 0.733; Ser,Pro,Orn,Lys,Phe, 0.73; Asn,Ala,Met,Orn,Leu, 0.73; Gln,Arg,Met,Leu,Phe, 0.726; Asn,Ala,Arg,Tyr,Phe, 0.726; Asn, Arg, Pro, Met, Leu, 0.726; Gly, Ala, Cyt, Met, Phe, 0.726; Gly, Arg, Tyr, Met, Trp, 0.725; Ser,Arg,Pro,Val,Met, 0.723; Gly, Gln, Arg, Met, Phe, 0.72; Ser, Arg, Orn, Lys, Phe, 0.72; Ala, Cyt, Lys, Leu, Phe, 0.718; Asn, Ala, Cyt, Met, Phe, 0.718; Ala,Cyt,Met,Orn,Lys, 0.718; Asn, Gly, Ala, Phe, Trp, 0.718; Ser, Gln, Arg, Orn, Phe, 0.716; Asn, Ala, Met, Orn, Lys, 0.716; Thr, Ala, Arg, Pro, Phe, 0.715; His, Arg, Pro, Val, Met, 0.715; Ala, Cit, Val, Met, Orn, 0.715; Thr, Ala, Cyt, Arg, Phe, 0.713; Asn, Gly, Ala, Orn, Ile, 0.713; Gly, Cyt, Arg, Pro, Phe, 0.713; Asn, Gln, Ala, Orn, Trp, 0.713; Ser, His, Ala, Arg, Phe, 0.713; Arg, Pro, Tyr, Val, Met, 0.711; Arg, Pro, Tyr, Met, Phe, 0.711; Ser, His, Ala, Arg, Tyr, 0.711; Gly,Gln,Ala,Met,Orn, 0.711; Gly,Thr,Arg,Orn,Phe, 0.709; Gly,Ala,Cit,Met,Leu, 0.709; Asn,Ala,Tyr,Iron,Lys, 0.708; Gly,Gln,Ala,Tyr,Iron, 0.708; Gly,Ala,Cit,Met,Orn, 0.708; Ser,Thr,Arg,Phe,Trp, 0.706; Asn,Ala,Arg,Orn,Lys, 0.706; Ser,Asn,Ala,Leu,Phe, 0.706; Asn,Ala,Tyr,Phe,Trp, 0.706; Asn,Pro,Orn,Phe,Trp, 0.704; Ala,Cit,Tyr,Leu,Phe, 0.704; His,Ala,Val,Met,Phe, 0.704; Ser,Ala,Met,Orn,Lys, 0.704; Ser,Asn,Arg,Phe,Trp, 0.703; Ser,Thr,Arg,Val,Phe, 0.703; Gly,Ala,Leu,Phe,Trp, 0.703; Ala,Cit,Met,Phe,Trp, 0.703; Arg,Val,Met,Phe,Trp, 0.701; Ser,Asn,Thr,Ala,Orn, 0.701; Gly,Ala,Val,Met,Orn, 0.701; Ser,Asn,Ala,Orn,Lys, 0.699; Arg,Pro,Val,Met,Orn, 0.699; Asn,Ala,Tyr,Iron,Leu, 0.699; Gly,Ala,Lys,Phe,Trp, 0.699; Ser,Cit,Arg,Leu,Phe, 0.698; Ser,Arg,Tyr,Val,Phe, 0.698; Gly,Arg,Leu,Phe,Trp, 0.696; Ser,His,Ala,Tyr,Orn, 0.689.

[0197] [315.You cannot see the light of the light of the light of the sun. Ala,Val,Met,Orn,Leu,Phe, 0.834; Gly,Ala,Met,Orn,Leu,Phe, 0.818; Ala,Arg,Met,Orn,Leu,Phe, 0.816; Ser,Ala,Met,Orn,Leu,Phe, 0.816; Ala,Pro,Met,Orn,Leu,Phe, 0.816; Ala,Met,Orn,Leu,Phe, Trp, 0.816; Ala,Met,Orn,Lys,Leu,Phe, 0.814; Thr,Ala,Met,Orn,Leu,Phe, 0.813; Ser,Gln,Ala,Tyr,Orn,Phe, 0.807; Gly,Ala,Val,Orn,Leu,Phe, 0.806; Ala,Met,Orn,Ile,Leu,Phe, 0.804; Gly, Gln, Ala, Pro, Orn, Phe, 0.804; Gly, His, Ala, Orn, Phe, Trp, 0.801; Gly, His, Ala, Tyr, Orn, Phe, 0.801; Ser,Gly,Ala,Met,Orn,Phe, 0.801; Gly, Gln, Ala, Orn, Lys, Phe, 0.801; Gly, Ala, Val, Met, Orn, Phe, 0.801; Ser, Ala, Cyt, Val, Orn, Phe, 0.801; Ser, Ala, Cyt, Orn, Ile, Phe, 0.801; Gly, Ala, Val, Orn, Phe, Trp, 0.799; Gly, His, Ala, Met, Orn, Phe, 0.797; Thr, Ala, Val, Orn, Leu, Phe, 0.797; Gln,Ala,Val,Orn,Leu,Phe, 0.797; Gly,His,Ala,Val,Orn,Phe, 0.796; Gln,Ala,Val,Met,Orn,Phe, 0.796; His,Ala,Pro,Met,Orn,Phe, 0.796; Ser,Ala,Arg,Met,Orn,Phe, 0.794; Ala,Arg,Val,Met,Leu,Phe, 0.791; Ala,Cit,Val,Met,Orn,Leu, 0.791; Ser,Thr,Ala,Orn,Phe,Trp, 0.791; His,Ala,Pro,Val,Orn,Phe, 0.789; Asn,Ala,Arg,Pro,Orn,Phe, 0.789; Gln,Ala,Arg,Met,Leu,Phe, 0.787; His,Ala,Val,Orn,Leu,Phe, 0.785; Ala,Arg,Orn,Ile,Leu,Phe, 0.785; His,Ala,Val,Orn,Ile,Phe, 0.784; Asn,Ala,Tyr,Val,Orn,Phe, 0.782; Asn,Ala,Orn,Lys,Phe,Trp, 0.782; Ala,Tyr,Val,Orn,Leu,Phe, 0.782; Gly,Ala,Arg,Val,Met,Leu, 0.779; Gln,Ala,Arg,Orn,Lys,Phe, 0.779; Gly,Ala,Arg,Pro,Met,Orn, 0.779; His,Ala,Cit,Met,Orn,Phe, 0.779; Gly,Ala,Arg,Pro,Met,Phe, 0.779; Thr,Ala,Tyr,Met,Orn,Phe, 0.777; Asn,Ala,Val,Orn,Phe,Trp, 0.775; Ala,Val,Met,Orn,Ile,Leu, 0.774; His,Ala,Arg,Ile,Leu,Phe, 0.772; Ala,Pro,Val,Orn,Leu,Phe, 0.772; Ala,Pro,Orn,Lys,Leu,Phe, 0.772; His,Ala,Val,Met,Orn,Leu, 0.77; Ala,Cit,Orn,Lys,Leu,Phe, 0.77; His,Ala,Orn,Ile,Phe,Trp, 0.77; Gly, Ala, Arg, Met, Lys, Phe, 0.77; Asn, Ala, Cyt, Orn, Lys, Phe, 0.77; Ala, Cyt, Val, Met, Leu, Phe, 0.77; Ala,Pro,Val,Orn,Lys,Phe, 0.77; Gly, Ala, Arg, Val, Met, Lys, 0.77; Gly, Thr, Ala, Arg, Met, Phe, 0.767; Gly, Ala, Arg, Val, Met, Phe, 0.765; Ala, Arg, Met, Lys, Leu, Trp, 0.764; Ser, Gly, Ala, Arg, Met, Phe, 0.762; Gln, Ala, Arg, Met, Ile, Trp, 0.762; Ser,Ala,Arg,Val,Met,Orn, 0.76; His, Ala, Arg, Tyr, Met, Ile, 0.758; Gly, Ala, Cyt, Arg, Pro, Met, 0.758; Gln, Ala, Arg, Tyr, Met, Orn, 0.757; Ser,Thr,Ala,Arg,Met,Orn, 0.755; Asn, Gly, Ala, Arg, Met, Trp, 0.755; His, Ala, Arg, Pro, Met, Phe, 0.755; Gly, Ala, Arg, Met, Ile, Trp, 0.753; Ala, Arg, Tyr, Orn, Lys, Phe, 0.753; Gly, Ala, Cyt, Arg, Val, Met, 0.753; Ser,Ala,Cit,Arg,Met,Leu, 0.752; Gln,Ala,Val,Met,Orn,Ile, 0.75; Asn,Ala,Arg,Tyr,Met,Ile, 0.75; Gly,His,Ala,Arg,Val,Met, 0.75; His,Ala,Met,Ile,Leu,Phe, 0.75; Thr,Ala,Cit,Arg,Met,Ile, 0.748; Gly,Gln,His,Ala,Arg,Phe, 0.747; Ser,Thr,Ala,Pro,Met,Orn, 0.747; Ala,Arg,Pro,Val,Orn,Phe, 0.745; Gln,Thr,Ala,Met,Orn,Leu, 0.745; Gly,Ala,Cit,Arg,Val,Phe, 0.745; Ala,Met,Orn,Lys,Leu,Trp, 0.745; Gly,Ala,Cit,Arg,Lys,Phe, 0.743; Gly,His,Ala,Arg,Phe,Trp, 0.742; His,Ala,Cit,Met,Orn,Leu, 0.74; Gln,Ala,Pro,Met,Orn,Leu, 0.738; Gln,His,Ala,Met,Orn,Leu, 0.736; Ser,Thr,Ala,Val,Met,Orn, 0.735; Thr,Ala,Met,Orn,Lys,Ile, 0.733; Ser,His,Ala,Cit,Leu,Phe, 0.733; Ala,Cit,Pro,Met,Orn,Leu, 0.731; Gln,Ala,Cit,Met,Orn,Trp, 0.731; His,Ala,Cit,Met,Orn,Ile, 0.73; His,Ala,Met,Orn,Ile,Leu, 0.73; His,Ala,Met,Orn,Lys,Ile, 0.726; Ser,Ala,Cit,Met,Orn,Trp, 0.72; Ser,His,Ala,Arg,Leu,Phe, 0.709.

[0198] [316. Two-variable equation obtained from amino acids and amino acid-related metabolites before the start of treatment with response rate as an evaluation index] hTrp,NP, 0.742; AnthA,NP, 0.726; Kyn, NP, 0.725; Pro,NP, 0.725; Ala,hTrp, 0.725; God,AnthA, 0,723; QA,NP, 0.72; Ala,Kyn, 0.72; Thr,NP, 0.715; Orn, NP, 0,713; Arg,NP, 0.706; hKyn, NP, 0.704; Lys,NP, 0.703; Arg,hTrp, 0.703; hTrp, AnthA, 0.701; Cit,NP, 0.699; hKyn, AnthA, 0.699; AnthA,Kyn, 0.698; Orn,hTrp, 0.693; Orn,hKyn, 0.693; Ala,NP, 0,691; Trp,NP, 0.689; Arg,hKyn, 0.689; AnthA,QA, 0,686; Arg,QA, 0.684; Pro,hKyn, 0.682; Arg, AnthA, 0.682; Pro,Kyn, 0.681; hTrp,QA, 0.677; Pro,hTrp, 0.677; Arg,Kyn, 0.677; Ala,hKyn, 0.676; God,Orn, 0,676; Pro,AnthA, 0.674; Light,Kyn, 0.672; hKyn,hTrp, 0.671; Thr,Arg, 0.671; Orn,QA, 0,666; Ala,Arg, 0.666; Cit,QA, 0.666; hTrp,Kyn, 0.664; Lys,AnthA, 0.662; Wing,QA, 0,662; Trp,hKyn, 0.66; Cit,hKyn, 0.654; Light,hKyn, 0.652; Cit,hTrp, 0.652; Arg,Orn, 0.652; Cit,AnthA, 0.652; Trp,Kyn, 0.652; Ala,Lys, 0,652; Trp,AnthA, 0.652; Orn,Kyn, 0.65; Lys,hTrp, 0.65; Ala,Cit, 0.65; Trp,hTrp, 0.649; Orn,AnthA, 0.649; Thr,hTrp, 0.645; Arg,Trp, 0.642; Arg,Pro, 0.642; Thr,God,642; Ala,Pro, 0.64; Arg,Lys, 0.639; Thr,hKyn, 0.637; Thr,AnthA, 0.637; Lys,QA, 0.635; hKyn,QA, 0.633; Thr,Kyn, 0.628; Orn,Lys, 0.623; Cit,Kyn, 0.622; Orn,Trp, 0.618; Kyn,QA, 0.617; Trp,QA, 0.615; Thr,Orn, 0.611; Cit,Pro, 0.606; Thr,QA, 0.605; Thr,Lys, 0.595; Cit,Lys, 0.588; Thr,Cit, 0.586; Cit,Trp, 0.586; Pro,Trp, 0.584; 0.571; Thr,Trp, 0.566.

[0199] [317. A three-variable formula derived from amino acids and amino acid-related metabolites before the start of treatment, with response rate as an evaluation index] Ala,AnthA,Kyn, 0.772; hTrp,AnthA,NP, 0.764; Ala,hKyn,AnthA, 0.76; Pro,hTrp,NP, 0.755; Ala, hTrp, AnthA, 0.753; Ala,hTrp,Kyn, 0.753; hTrp,Kyn,NP, 0.75; Pro,hTrp,AnthA, 0.75; Ala,hTrp,NP, 0.75; Ala,AnthA,NP, 0.748; Arg,hTrp,NP, 0.747; hTrp,QA,NP, 0.745; Pro,AnthA,NP, 0.745; Pro, hTrp, Kyn, 0.743; Pro,hKyn,hTrp, 0.742; Ala,Orn,Kyn, 0.742; Ala,AnthA,QA, 0.74; Pro,hKyn,AnthA, 0.74; Thr,hTrp,NP, 0.738; Thr,Ala,AnthA, 0.738; hTrp, AnthA, Kyn, 0.736; Cit,hTrp,QA, 0.735; Pro,Kyn,NP, 0.735; Ala,Lys,AnthA, 0.735; Pro, AnthA, Kyn, 0.735; Orn,hKyn,hTrp, 0.733; hKyn, hTrp, NP, 0.733; Ala,Kyn,NP, 0.731; Lys,AnthA,NP, 0.73; hKyn, hTrp, AnthA, 0.73; Ala,Cit,hTrp, 0.73; hTrp,AnthA,QA, 0.728; Ala,hTrp,QA, 0.728; Ala,Arg,hTrp, 0.728; Trp,AnthA,NP, 0.728; Arg,AnthA,NP, 0.728; Ala,Cit,Kyn, 0.728; Pro,hTrp,QA, 0.726; Cit,AnthA,NP, 0.726; Ala,Trp,AnthA, 0.726; AnthA,Kyn,NP, 0.726; Pro,Orn,hKyn, 0.725; Arg, AnthA, Kyn, 0.725; AnthA,QA,NP, 0.725; Ala,Arg,Kyn, 0.725; Pro,QA,NP, 0.723; Ala,Arg,AnthA, 0.723; Ala,Orn,NP,723; Ala,Trp,Kyn, 0.723; hKyn, AnthA, NP, 0.723; Ala,Pro,Kyn, 0.723; Cit,hTrp,AnthA, 0.721; Pro,hKyn,NP, 0.721; Pro,hKyn,Kyn, 0.721; Trp, hTrp, AnthA, 0.72; Ala,Pro,AnthA, 0.72; Orn, hTrp, AnthA, 0.718; Arg,Kyn,NP, 0.718; God,Cit,AnthA, 0.718; Ala,Orn,hKyn, 0.718; Ala,Orn,QA, 0,718; Ala,Lys,Kyn, 0.718; Trp, AnthA, Kyn, 0.716; Cit,hKyn,NP, 0.715; Trp,hTrp,NP, 0.713; Orn,hKyn,AnthA, 0.713; Pro,AnthA,QA, 0.713; Cit,Kyn,NP, 0.711; Orn, AnthA, NP, 0.711; Thr,Arg,AnthA, 0.709; Trp,hTrp,Kyn, 0.709; Arg,QA,NP, 0.709; Light, AnthA, Kyn, 0.709; Lys,hTrp,AnthA, 0.706; Arg,AnthA,QA, 0.706; Wing,Pro,NP, 0.704; Cit,QA,NP, 0.704; Orn,AnthA,QA, 0.703; Trp, hKyn, hTrp, 0.701; Ala,Arg,NP, 0.701; Ala,Lys,NP, 0.701; Cit,hKyn,AnthA, 0.701; Ala,Trp,NP, 0.699; Arg,hKyn,NP, 0.699; Wing,QA,NP, 0,699; hKyn,AnthA,QA, 0.698; Thr,hKyn,AnthA, 0.698; Cit,Arg,AnthA, 0.696; Ala, hKyn, NP, 0.694; Trp,hKyn,NP, 0.693; AnthA,Kyn,QA, 0.693; Lys,AnthA,QA, 0.688; Thr,Pro,AnthA, 0.686; Arg,Pro,AnthA, 0.681; Arg, Trp, AnthA, 0.674; Thr,AnthA,QA,674; Cit,Pro,AnthA, 0.672; Pro,Lys,AnthA, 0.671; Cit,AnthA,QA, 0.671; Pro,Trp,AnthA, 0.669.

[0200] [318. A four-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment, with response rate as an evaluation index] Ala, hTrp, AnthA, NP, 0.787; Ala, hTrp, AnthA, Kyn, 0.784; Thr,Ala,AnthA,Kyn, 0.784; Pro, hTrp, AnthA, NP, 0.782; Ala,Lys,hTrp,AnthA, 0.78; Ala,Pro,AnthA,Kyn, 0.78; Pro, hKyn, hTrp, AnthA, 0.779; Ala, Trp, AnthA, Kyn, 0.779; Ala,Arg,AnthA,Kyn, 0.775; Ala,Pro,hTrp,Kyn, 0.774; Pro,hKyn,hTrp,Kyn, 0.774; Ala,Lys,hTrp,NP, 0.774; Ala,Orn,hKyn,hTrp, 0.774; Thr,Ala,Pro,AnthA, 0.772; Ala,AnthA,Kyn,NP, 0.772; Ala, Orn, hTrp, AnthA, 0.772; Ala, Lys, AnthA, Kyn, 0.772; Thr,Ala,hTrp,AnthA, 0.77; Ala,hKyn,AnthA,Kyn, 0.77; Cit, hTrp, AnthA, NP, 0.77; Ala, Orn, AnthA, Kyn, 0.767; Ala,AnthA,Kyn,QA, 0.767; Ala,Lys,hTrp,Kyn, 0.767; Ala, Orn, hTrp, NP, 0.767; Ala,Orn,AnthA,NP, 0.765; Arg,hTrp,AnthA,NP, 0.765; Cit,hTrp,Kyn,NP, 0.765; Ala,Cit,hTrp,NP, 0.764; Ala,Orn,hTrp,QA, 0.762; Ala,hKyn,hTrp,NP, 0.762; Ala,hTrp,Kyn,NP, 0.76; Ala, Trp, hKyn, AnthA, 0.76; Pro, hKyn, AnthA, NP, 0.758; Arg,Pro,hTrp,Kyn, 0.758; hKyn, hTrp, AnthA, NP, 0.757; Thr, hTrp, AnthA, NP, 0.757; Thr,Ala,hTrp,NP, 0.757; Ala,Orn,Kyn,NP, 0.757; Pro, hTrp, QA, NP,757; Ala,Cit,hKyn,AnthA, 0.755; Ala, Trp, AnthA, NP, 0.755; Pro, hTrp, AnthA, QA, 0.753; Ala,Pro,hKyn,AnthA, 0.753; Ala,Orn,hKyn,AnthA, 0.753; Wing,Lys,AnthA,QA, 0.753; Ala,hTrp,Kyn,QA, 0.753; Thr,Ala,Arg,AnthA, 0.753; Pro,hKyn,hTrp,NP, 0.753; Thr,Ala,Lys,AnthA, 0.753; Trp, hTrp, AnthA, Kyn, 0.753; Ala,AnthA,QA,NP, 0,752; Arg,Pro,hTrp,AnthA, 0.752; Pro, Trp, AnthA, NP, 0.752; Thr,Ala,Trp,AnthA, 0.752; Pro, Orn, hTrp, NP, 0.752; Cit,Pro,hTrp,NP, 0.752; Pro,hKyn,AnthA,Kyn, 0.75; Ala,Pro,hTrp,NP, 0.75; Arg, AnthA, Kyn, NP, 0.75; Arg,Pro,hKyn,AnthA, 0.747; Thr,Ala,hKyn,AnthA, 0.747; Pro,AnthA,Kyn,NP, 0.747; Ala,Orn,AnthA,QA, 0,747; Pro,AnthA,QA,NP, 0.747; Thr, Pro, hTrp, Kyn, 0.747; Ala, Orn, Trp, AnthA, 0.747; Pro, Trp, hTrp, Kyn, 0.747; Ala,hTrp,QA,NP, 0.747; Ala,Arg,Lys,AnthA, 0.747; Trp, hKyn, hTrp, AnthA, 0.745; Arg,Pro,AnthA,NP, 0.745; Lys, hKyn, hTrp, AnthA, 0.745; Pro,Lys,hTrp,Kyn, 0.745; Ala,Pro,Lys,AnthA, 0.745; Ala,Cit,Lys,AnthA, 0.745; Pro,Trp,hKyn,AnthA, 0.743; Ala,Arg,AnthA,NP, 0.743; Cit , Pro , hKyn , AnthA ,742; Ala,Pro,AnthA,NP, 0.742; Ala,Trp,AnthA,QA, 0.742; Cit,hTrp,AnthA,QA, 0.742; Ala,Lys,Trp,AnthA, 0.742; Pro,Lys,hKyn,AnthA, 0.738; Ala,Pro,AnthA,QA, 0.738; Cit,hKyn,AnthA,NP, 0.738; Ala,Arg,AnthA,QA, 0.736; Lys,hKyn,AnthA,NP, 0.736; Ala,Cit,Kyn,NP, 0.736; Pro,Trp,AnthA,Kyn, 0.735; Ala,Cit,Orn,AnthA, 0.735; hKyn,hTrp,AnthA,QA, 0.731; Trp,hKyn,AnthA,NP, 0.725; Thr,Trp,hKyn,AnthA, 0.721; Arg,Trp,hKyn,AnthA, 0.715; Trp,hKyn,AnthA,Kyn, 0.713; Cit,Trp,hKyn,AnthA, 0.711; Trp,hKyn,AnthA,QA, 0.711; Pro,Trp,AnthA,QA, 0.711; Lys,Trp,hKyn,AnthA, 0.706; Pro,Lys,AnthA,QA, 0.706.

[0201] [319. A five-variable formula derived from amino acids and amino acid-related metabolites before the start of treatment, with response rate as an evaluation index] Thr,Ala,Cit,hTrp,Kyn, 0.801; Thr,Pro,hTrp,AnthA,NP, 0.797; Ala,Trp,hTrp,AnthA,NP, 0.797; Ala, Trp, hTrp, AnthA, Kyn, 0.796; Ala,Orn,Lys,hTrp,AnthA, 0.796; Ala,Cit,hTrp,Kyn,NP, 0.796; Ala,Lys,hTrp,AnthA,Kyn, 0.794; Thr, Pro, hKyn, hTrp, AnthA, 0.794; Ala,Lys,hTrp,AnthA,NP, 0.794; Ala,Pro,hTrp,AnthA,Kyn, 0.791; Thr,Ala,Orn,AnthA,Kyn, 0.791; Thr,Ala,Orn,hTrp,Kyn, 0.791; Thr,Ala,hTrp,AnthA,NP, 0.789; Pro,Trp,hKyn,hTrp,AnthA, 0.789; Ala,hTrp,AnthA,Kyn,QA, 0.789; Ala,hKyn,hTrp,AnthA,NP, 0.789; Ala,Pro,hTrp,AnthA,NP, 0.789; Ala,Arg,Orn,hTrp,Kyn, 0.789; Pro, Lys, hKyn, hTrp, AnthA, 0.787; Ala, Orn, hTrp, AnthA, NP, 0.787; Pro,Lys,hTrp,AnthA,NP, 0.787; Ala,Cit,Orn,hTrp,Kyn, 0.787; Pro, Orn, hKyn, hTrp, AnthA, 0.785; Arg, Pro, hTrp, AnthA, NP, 0.785; Cit,Pro,hTrp,AnthA,NP, 0.785; Ala,hTrp,AnthA,Kyn,NP, 0.784; Thr,Ala,Pro,hTrp,AnthA, 0.784; Ala,hTrp,AnthA,QA,NP, 0.784; Ala,Pro,Orn,hTrp,Kyn, 0.784; Thr,Ala,AnthA,Kyn,QA, 0.784; Ala,Pro,Trp,hTrp,Kyn, 0.784; Thr,Ala,Arg,AnthA,Kyn, 0.782; Ala,Cit,Arg,hTrp,Kyn,782; Thr,Ala,AnthA,Kyn,NP, 0.78; Pro, Orn, hTrp, AnthA, NP, 0.78; Thr,Ala,Lys,hTrp,AnthA, 0.78; Ala,Pro,Lys,AnthA,Kyn, 0.78; Thr,Ala,Trp,AnthA,Kyn, 0.78; Ala,Cit,hKyn,hTrp,Kyn, 0.78; Thr,Pro,hTrp,AnthA,Kyn, 0.779; Pro,hTrp,AnthA,Kyn,QA, 0.779; Ala, Arg, Orn, hTrp, AnthA, 0.779; Ala,Pro,Orn,hTrp,AnthA, 0.779; Ala, Orn, Trp, AnthA, Kyn, 0.779; Ala,Pro,AnthA,Kyn,QA, 0.779; Pro, hKyn, hTrp, AnthA, QA, 0.777; Pro,hKyn,hTrp,AnthA,Kyn, 0.774; Arg, Pro, hKyn, hTrp, AnthA, 0.774; Pro,Trp,hTrp,AnthA,Kyn, 0.774; Thr,Pro,hTrp,AnthA,QA, 0.774; Ala,Trp,hTrp,AnthA,QA, 0.774; Ala,Cit,hTrp,AnthA,QA, 0.774; Ala,Cit,AnthA,Kyn,NP, 0.774; Ala,Lys,AnthA,Kyn,QA, 0.774; Ala,Arg,Lys,AnthA,Kyn, 0.774; Ala,Orn,AnthA,Kyn,QA, 0.772; Ala,Orn,hKyn,hTrp,AnthA, 0.772; Pro, Orn, hTrp, AnthA, Kyn, 0.772; Thr,Arg,Pro,hKyn,AnthA, 0.772; Pro,Lys,hTrp,AnthA,Kyn, 0.769; Cit,Pro,hTrp,AnthA,Kyn, 0.769; Thr,Pro,hKyn,AnthA,NP, 0.769; Thr,Ala,Arg,AnthA,NP, 0.769; Thr,Pro,Trp,hKyn,AnthA, 0.769; Ala,AnthA,Kyn,QA,NP, 0.769; Thr,Pro,hKyn,AnthA,QA,769; Ala,Cit,Orn,hTrp,AnthA, 0.769; Thr,Cit,Pro,hKyn,AnthA, 0.769; Thr,Ala,hKyn,hTrp,AnthA, 0.767; Ala,Arg,hTrp,AnthA,QA, 0.767; Pro,Trp,hTrp,AnthA,QA, 0.767; Ala,Arg,AnthA,Kyn,NP, 0.767; Ala,Orn,hKyn,AnthA,Kyn, 0.767; Thr,Ala,Pro,AnthA,QA, 0.767; Ala,hTrp,Kyn,QA,NP, 0.767; Arg,Pro,Orn,hKyn,AnthA, 0.765; Cit,Pro,hTrp,AnthA,QA, 0.765; Ala,Cit,Orn,AnthA,Kyn, 0.765; Ala,Cit,hKyn,AnthA,Kyn, 0.765; Thr,Pro,hTrp,Kyn,NP, 0.764; Ala,Trp,hKyn,AnthA,NP, 0.764; Ala,Lys,AnthA,QA,NP, 0.764; Thr,Ala,Orn,AnthA,NP, 0.762; Thr,Ala,hTrp,Kyn,NP, 0.762; Ala,Cit,Pro,hTrp,AnthA, 0.762; Pro,Trp,hKyn,AnthA,NP, 0.76; Ala,Lys,hKyn,AnthA,NP, 0.758; Pro,hKyn,AnthA,QA,NP, 0.757; Thr,Ala,Trp,AnthA,NP, 0.757; Cit,Pro,Orn,hKyn,AnthA, 0.757; Pro,Orn,hKyn,AnthA,NP, 0.755; Ala,Pro,Orn,hKyn,AnthA, 0.755; Ala,Orn,Lys,AnthA,NP, 0.755; Ala,Arg,hKyn,AnthA,NP, 0.753; Ala,Arg,Orn,hKyn,AnthA, 0.753; Ala,Cit,Pro,hKyn,AnthA, 0.752; Ala,Arg,Pro,hTrp,AnthA, 0.748; Ala,Pro,hKyn,AnthA,QA, 0.748; Pro,Orn,hKyn,AnthA,QA, 0.748; Pro,Orn,Trp,hKyn,AnthA, 0.745.

[0202] [320. A six-variable equation derived from amino acids and amino acid-related metabolites before the start of treatment, with the response rate as an evaluation index] Thr,Ala,Orn,hTrp,AnthA,Kyn, 0.823; Ala, Arg, Orn, hTrp, AnthA, Kyn, 0.816; Ala,Pro,Trp,hTrp,AnthA,NP, 0.816; Thr,Ala,Cit,hTrp,AnthA,Kyn, 0.813; Thr,Pro,Orn,hKyn,hTrp,AnthA, 0.807; Thr,Ala,Orn,hTrp,AnthA,QA, 0.807; Thr,Ala,Pro,Orn,AnthA,Kyn, 0.807; Thr,Ala,Orn,Lys,hTrp,AnthA, 0.807; Ala,Cit,Trp,hTrp,Kyn,NP, 0.807; Ala,Orn,Trp,hTrp,AnthA,Kyn, 0.806; Ala,Arg,Orn,hTrp,AnthA,NP, 0.806; Ala, Orn, hTrp, AnthA, Kyn, QA, 0.806; Ala,Orn,Lys,hTrp,AnthA,QA, 0.806; Ala,Pro,Lys,hTrp,AnthA,Kyn, 0.802; Thr,Pro,hTrp,AnthA,Kyn,NP, 0.802; Thr,Ala,Pro,hKyn,hTrp,AnthA, 0.802; Thr,Ala,Cit,Orn,hTrp,Kyn, 0.802; Thr,Ala,Orn,hTrp,AnthA,NP, 0.801; Ala,Pro,Orn,hTrp,AnthA,Kyn, 0.801; Thr,Ala,Trp,hTrp,AnthA,Kyn, 0.801; Pro,Orn,Lys,hKyn,hTrp,AnthA, 0.801; Pro, Orn, Trp, hKyn, hTrp, AnthA, 0.801; Arg, Pro, Trp, hTrp, AnthA, NP, 0.801; Thr,Ala,hKyn,hTrp,AnthA,Kyn, 0.799; Thr,Cit,Pro,hKyn,hTrp,AnthA, 0.799; Ala,Cit,hTrp,AnthA,Kyn,NP, 0.797; Thr, Pro, Trp, hKyn, hTrp, AnthA, 0.797; Ala,Orn,Lys,hTrp,Kyn,NP, 0.797; Ala,Cit,hKyn,hTrp,AnthA,Kyn,797; Ala,Trp,hTrp,AnthA,QA,NP, 0.797; Thr,Ala,Arg,Orn,hTrp,AnthA, 0.797; Thr,Ala,Pro,hTrp,AnthA,QA, 0.796; Ala,Lys,hKyn,hTrp,AnthA,NP, 0.796; Ala,Arg,Lys,hTrp,AnthA,NP, 0.796; Ala,Cit,hTrp,AnthA,Kyn,QA, 0.796; Ala,Arg,Trp,hTrp,AnthA,Kyn, 0.796; Ala,Trp,hTrp,AnthA,Kyn,QA, 0.796; Thr,Ala,Arg,Lys,hTrp,AnthA, 0.796; Thr,Ala,Cit,Orn,AnthA,Kyn, 0.796; Ala,Cit,Orn,hTrp,Kyn,NP, 0.796; Thr,Ala,hTrp,AnthA,Kyn,NP, 0.794; Thr,Ala,Cit,hTrp,Kyn,NP, 0.794; Thr,Ala,hTrp,AnthA,Kyn,QA, 0.794; Ala,Lys,hTrp,AnthA,Kyn,QA, 0.794; Thr,Ala,Cit,hTrp,AnthA,QA, 0.794; Thr,Ala,Cit,Lys,hTrp,Kyn, 0.794; Thr,Ala,Lys,hTrp,AnthA,Kyn, 0.792; Pro,Lys,hKyn,hTrp,AnthA,NP, 0.792; Thr,Pro,Lys,hTrp,AnthA,NP, 0.792; Thr,Arg,Pro,hTrp,AnthA,Kyn, 0.792; Ala,Cit,Arg,hTrp,Kyn,NP, 0.792; Ala,Cit,Lys,hTrp,AnthA,QA, 0.792; Thr,Ala,Cit,Lys,hTrp,AnthA, 0.792; Thr,Pro,hKyn,hTrp,AnthA,NP, 0.791; Cit,Pro,Lys,hKyn,hTrp,AnthA, 0.791; Thr,Ala,Pro,Lys,AnthA,Kyn, 0.791; Thr,Ala,Arg,Orn,AnthA,Kyn, 0.791; Ala,Cit,Arg,hTrp,AnthA,Kyn,789; Ala,Pro,Lys,hTrp,AnthA,QA, 0.789; Ala,Orn,Lys,AnthA,Kyn,NP, 0.789; Ala,Pro,Lys,hKyn,hTrp,AnthA, 0.787; Thr,Cit,Pro,hTrp,AnthA,Kyn, 0.787; Thr,Ala,Orn,AnthA,QA,NP, 0.787; Ala,Cit,Orn,Lys,hTrp,Kyn, 0.787; Pro,Trp,hKyn,hTrp,AnthA,NP, 0.785; Ala,Arg,hKyn,hTrp,AnthA,Kyn, 0.785; Ala,Cit,Pro,Lys,hTrp,Kyn, 0.785; Ala,Pro,hTrp,AnthA,QA,NP, 0.785; Thr,Ala,Orn,Lys,AnthA,Kyn, 0.785; Thr,Ala,Lys,AnthA,Kyn,NP, 0.785; Arg, Pro, Orn, hTrp, AnthA, NP, 0.785; Cit,Pro,hTrp,AnthA,QA,NP, 0.785; Ala,Cit,Lys,hKyn,hTrp,Kyn, 0.785; Thr,Ala,Trp,hTrp,AnthA,NP, 0.784; Ala,Arg,hTrp,AnthA,Kyn,QA, 0.784; Thr,Ala,Pro,Lys,hTrp,Kyn, 0.784; Ala,Cit,hTrp,AnthA,QA,NP, 0.784; Thr,Ala,Trp,hTrp,AnthA,QA, 0.782; Thr,Ala,Cit,hKyn,AnthA,Kyn, 0.782; Thr,Ala,Orn,hKyn,AnthA,NP, 0.78; Thr,Ala,Pro,Orn,hKyn,AnthA, 0.779; Ala,Arg,Pro,Lys,hTrp,AnthA, 0.779; Ala,Arg,Pro,Lys,hTrp,Kyn, 0.779; Ala, Arg, Pro, hKyn, hTrp, AnthA, 0.777; Thr,Ala,Pro,hTrp,Kyn,NP, 0.777; Ala,Cit,hKyn,hTrp,AnthA,QA, 0.777; Ala, Pro, Orn, AnthA, Kyn, NP,777; Ala,Arg,Orn,hKyn,hTrp,AnthA, 0.775; Arg,Pro,hTrp,AnthA,Kyn,QA, 0.775; Thr,Ala,Arg,hTrp,Kyn,NP, 0.775; Thr,Pro,Trp,hTrp,AnthA,Kyn, 0.774; Thr,Ala,Pro,Orn,AnthA,NP, 0.774; Ala,Cit,Arg,hTrp,AnthA,QA, 0.774; Arg,Pro,Orn,hKyn,AnthA,NP, 0.774; Ala,Pro,Orn,Lys,AnthA,Kyn, 0.774; Thr,Ala,Cit,hKyn,AnthA,NP, 0.772; Thr,Pro,Trp,hTrp,AnthA,QA, 0.77; Thr,Pro,hKyn,AnthA,QA,NP, 0.769; Thr,Ala,Trp,hKyn,hTrp,AnthA, 0.767; Thr,Ala,Pro,AnthA,QA,NP, 0.767.

Claims

1. an evaluation step of evaluating the pharmacological action of the immune checkpoint inhibitor in the subject using a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of the subject, or a formula including variables into which the concentration value is substituted and a value of the formula calculated using the concentration value; An evaluation method characterized by:

2. The blood is collected from the subject before or after treatment with the immune checkpoint inhibitor is started; the evaluation step evaluates the effect of the treatment in the evaluation subject; The evaluation method according to claim 1,

3. The blood is collected from the subject before treatment with the immune checkpoint inhibitor is started, the evaluation step evaluates a risk of side effects caused by the treatment in the evaluation subject; The evaluation method according to claim 1 or 2,

4. the evaluating step is executed by a control unit of an information processing device including a control unit; The evaluation method according to any one of claims 1 to 3,

5. a calculation step of calculating a value of the formula for evaluating the pharmacological action of an immune checkpoint inhibitor using a formula including a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of the subject to be evaluated, and a variable into which the concentration value is substituted; A calculation method characterized by:

6. The blood is collected from the subject before or after treatment with the immune checkpoint inhibitor is started; the formula is for assessing the efficacy of the treatment; The calculation method according to claim 5 ,

7. The blood is collected from the subject before treatment with the immune checkpoint inhibitor is started, The formula is for evaluating the risk of side effects caused by the treatment; The calculation method according to claim 5 or 6, characterized in that:

8. the calculation step is executed by a control unit of an information processing device including a control unit; 8. The calculation method according to claim 5, wherein

9. An evaluation device including a control unit, The control unit is An evaluation means for evaluating the pharmacological action of an immune checkpoint inhibitor in a subject, using a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of the subject, or a formula including variables into which the concentration value is substituted and a value of the formula calculated using the concentration value. To have An evaluation device comprising:

10. a terminal device that provides concentration data relating to the concentration value or the value of the formula via a network; The control unit is a data receiving means for receiving the concentration data or the value of the formula transmitted from the terminal device; a result transmission means for transmitting the evaluation result obtained by the evaluation means to the terminal device; Further equipped with the evaluation means uses the concentration value or the value of the formula included in the concentration data received by the data receiving means; The evaluation device according to claim 9 .

11. A calculation device including a control unit, The control unit is A calculation means for calculating a value of a formula for evaluating a pharmacological action of an immune checkpoint inhibitor, the formula including a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of a subject to be evaluated, and a variable into which the concentration value is substituted, the calculation means calculating a value of the formula using the formula. To have A calculation device comprising:

12. An evaluation program to be executed in an information processing device having a control unit, To be executed in the control unit, An evaluation step of evaluating the pharmacological action of the immune checkpoint inhibitor in the subject using a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of the subject, or a formula including variables into which the concentration value is substituted and a value of the formula calculated using the concentration value. containing, An evaluation program that features:

13. A calculation program to be executed in an information processing device having a control unit, To be executed in the control unit, A calculation step of calculating the value of the formula using a formula for evaluating the pharmacological action of an immune checkpoint inhibitor, the formula including a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of the subject to be evaluated, and a variable into which the concentration value is substituted. containing, A calculation program comprising:

14. A computer-readable recording medium having the program according to claim 12 or 13 recorded thereon.

15. An evaluation system configured by connecting an evaluation device having a control unit and a terminal device having a control unit via a network so as to be able to communicate with each other, The control unit of the terminal device a data transmitting means for transmitting to the evaluation device concentration data on a concentration value of at least one metabolite selected from Glu, Arg, Orn, Cit, His, Val, Phe, Tyr, Met, Pro, Asn, Leu, Lys, Thr, Ile, Gln, Ala, Ser, a-ABA, Trp, Gly, AnthA, hAnthA, hIAA, hKyn, hTrp, IAA, ILA, Kyn, KynA, NFKyn, NP, PA, QA, Serot, and XA in the blood of the evaluation subject, or a formula including variables into which the concentration value is substituted and a value of the formula calculated using the concentration value; A result receiving means for receiving an evaluation result regarding the pharmacological action of the immune checkpoint inhibitor transmitted from the evaluation device; Equipped with The control unit of the evaluation device a data receiving means for receiving the concentration data or the value of the formula transmitted from the terminal device; evaluation means for evaluating the pharmacological effect of the immune checkpoint inhibitor in the subject using the concentration value or the value of the formula included in the concentration data received by the data receiving means; a result transmission means for transmitting the evaluation result obtained by the evaluation means to the terminal device; To have A rating system characterized by:

Images