TWI228980B

TWI228980B - Process of creating an index for diagnosis or prognosis purpose

Info

Publication number: TWI228980B
Application number: TW91117315A
Authority: TW
Inventors: Ching-Hsiang Hsu
Original assignee: Taimont Biotech Inc
Priority date: 2002-08-01
Filing date: 2002-08-01
Publication date: 2005-03-11

Abstract

The present invention mainly relates to a process of creating an index for diagnosis and/or prognosis of a complex disease trait by using a correlation formula obtained by the statistic analysis and regression process for condition scores and the expression values of the gene selected to be related to the complex disease trait. A process of creating an asthma index for diagnosis and/or prognosis of asthma is also provided in the invention.

Description

1228980 Α7 Β7 五、發明説明ς 發明領域本發明王要是有關建立診斷及/或預判複合性基因疾病 (如氣喘）指數之方法。發明背景基因體醫學（genomic medicine)可定義為使用基因型分析以提升醫藥保健品質之學門，其包含疾病之病徵前鑑定、預防介入、藥物療法之選擇及根據個人基因型而設計的醫療保健方式。由於人體基因組及分子醫藥學之快速發展而使基因體醫學日益重要。現今在診斷或治療由單一基因扮演主要角色之疾病中，基因型分析已變成標準流程，但目前尚未利用基因型分析於診斷或治療涉及多重基因及非基因因素之複合性基因疾病上。一般相信複合性基因疾病（亦稱為多因素疾病）與多重基因、非基因因素、以及多重基因及非基因因素間交互作用有關’例如’第一型糖尿病（或胰島素依存性糖尿病）已被報導與至少10個基因有關（包含HLA區域及胰島素基因），而非僅與單一基因有關。據報導’氣喘與許多基因有關（j〇〇s L及Stanford AJ， Genotype predictors of response to asthma medications. Current Opinion in Pulmonary 2002; 8.9-15，Quinzii C 等人，Predictive genetic testing-new possibilities in determination of risk of complex diseases. Croatian Medical Journal, 200 1;42(4):45 8-462)，與氣喘有關之這些基因可調節 ________________- 4 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 x 297公釐） 1228980 A7 B7 五、發明説明（2 )1228980 Α7 Β7 V. Description of the invention The field of the invention The invention relates to a method for establishing a diagnostic and / or predictive index of a complex genetic disease (such as asthma). BACKGROUND OF THE INVENTION Genomic medicine can be defined as the use of genotype analysis to improve the quality of medical care, including pre-symptom identification of disease, preventive intervention, choice of drug therapy, and medical care designed based on individual genotypes the way. The rapid development of the human genome and molecular medicine has made genomic medicine increasingly important. Today, genotyping has become a standard procedure in the diagnosis or treatment of diseases in which a single gene plays a major role, but genotyping has not yet been used to diagnose or treat complex genetic diseases involving multiple genetic and non-genetic factors. It is generally believed that multiple genetic diseases (also known as multifactorial diseases) are related to multiple genes, nongenetic factors, and interactions between multiple genetic and nongenetic factors, such as type 1 diabetes (or insulin-dependent diabetes) has been reported. Associated with at least 10 genes (including HLA regions and insulin genes), not just a single gene. Asthma has been reported to be associated with many genes (j〇〇s L and Stanford AJ, Genotype predictors of response to asthma medications. Current Opinion in Pulmonary 2002; 8.9-15, Quinzii C et al., Predictive genetic testing-new possibilities in determination of risk of complex diseases. Croatian Medical Journal, 200 1; 42 (4): 45 8-462), these genes related to asthma can be regulated ________________- 4-This paper applies Chinese National Standard (CNS) Α4 specifications (210 x 297 mm) 1228980 A7 B7 V. Description of the invention (2)

Thl 及丁 h2 細胞之細胞素平衡（Rogge L 等人， Transcript imaging of the development of human T helper cells using oligonucleotide arrays. Nat Gen"，20 0 0;25( 1 ):96- 1 0 1 )。此外，謗發氣喘之非基因因素則包含有過敏原（如花粉、黴菌孢子、動物毛髮或粉塵）、感染（如病毒、細菌或謗發空氣道發炎之黴菌的感染）、溫度變化、藥物（如0-腎上腺素拮抗劑或阿斯匹靈）、某些食用色素、運動、情緒及其他因素（如油漆、香料、香煙、空氣污染、經期改變或胃食道逆流疾病）。由於複合性基因疾病與許多基因因素及非基因因素有關，因此患有複合性基因疾病之病患會出現不同病徵，此可能是由於個體、環境、年齡、病理學因素及疾病種類差異所造成。迄今，診斷複合性基因疾病（如氣喘）並無標準規範（Britton J 及 Lewis S，Objective measures and the diagnosis of asthma. BMJ 1 998; 3 1 7:227-228 ; Talor DR, Making the diagnosis of asthma. BMJ 1 9 9 7 ; 3 1 5 : 4 - 5 )。即使建立了一些標準診斷規範，仍無法有效地鑑定出複合性基因疾病，因此無法使用在臨床上。大多數醫師鑑定複合性基因疾病係組合使用病歷史、身體檢查、試驗檢測及/或放射線診斷。然而，此診斷方法往往由於缺乏整體考量或缺乏經驗而誤判，又有些複合性基因疾病由於其病徵會被誤診為其他疾病而無法鑑定出。一般相信病歷史並非客觀之指數，此係因為孩童或老年人難以提供完整的病史記憶或病徵之描述。此外，由於病圆一一·丨一 -5- 本紙張尺度適用中國國家標準(CNS)八4規格x297公爱) — '—' -裝訂The cytokine balance of Thl and D2 cells (Rogge L et al., Transcript imaging of the development of human T helper cells using oligonucleotide arrays. Nat Gen ", 20 0; 25 (1): 96- 1 0 1). In addition, non-genetic factors that cause asthma include allergens (such as pollen, mold spores, animal hair or dust), infections (such as viruses, bacteria, or airborne inflammation of molds), temperature changes, drugs ( (Such as 0-adrenaline antagonists or aspirin), certain food coloring, exercise, mood and other factors (such as paint, spices, cigarettes, air pollution, menstrual changes or gastroesophageal reflux disease). Because complex genetic diseases are related to many genetic and non-genetic factors, patients with complex genetic diseases will have different symptoms. This may be due to differences in individuals, environment, age, pathological factors, and types of diseases. To date, there is no standard specification for the diagnosis of complex genetic diseases such as asthma (Britton J and Lewis S, Objective measures and the diagnosis of asthma. BMJ 1 998; 3 1 7: 227-228; Talor DR, Making the diagnosis of asthma BMJ 1 9 9 7; 3 1 5: 4-5). Even if some standard diagnostic criteria are established, composite genetic diseases cannot be effectively identified and therefore cannot be used clinically. Most physicians identify a combination of genetic diseases that use a combination of history, physical examination, laboratory tests, and / or radiological diagnosis. However, this diagnostic method is often misdiagnosed due to lack of overall consideration or lack of experience, and some complex genetic diseases cannot be identified because their symptoms are misdiagnosed as other diseases. It is generally believed that history is not an objective index because it is difficult for a child or an elderly person to provide a complete description of the history or symptoms. In addition, due to illness, one-to-one, one-to-one -5- This paper size applies to China National Standard (CNS) 8-4 x297 public love) — '—'-binding

線 1228980 A7 B7 五、發明説明（3 ) 患以不同方式描述病徵，有時醫師亦無法作正確的診斷。已有一些研究係依據基因分析而企圖用以診斷複合性基因疾病（Quinzii C 等人，Predictive genetic testing-new possibilities in determination of risk of complex diseases . CMJ, 200 1 ;42(4) :45 8-462 ; Joos L 及 Stanford AJ，Genotype predictors of response to asthma medications. Current opinion in pulmonary medicine 2002; 8:9-15 ； Brutsche MH 等人，Array-based diagnostic gene-expression score for atopy and asthma. J allergy Clin Immunol 2002; 1 09:27 1 -273 ，Sheppard D，Uses of expression microarrays in studies of pulmonary fibrosis， asthma，acute lung injury，and emphysema. Chest 2002, 121(Sup3):21S-25S)。但是，該等研究均著重於與複合性基因疾病有關之少數基因，且均未揭示多重基因之關聯性。Brutsche MH等人提供一種評分指數，稱為「複合過敏性基因表現（Composite Atopy Gene Expression (CAGE))」指數，供作過敏性及氣喘之診斷。該CAGE指數意指病患及「健康者」間在1〇個基因表現上之整體差異。然而，該CAGE指數並非良好的診斷指標，此係因為具有不同功能之基因提供不同程度之功能’此外’亦有「健康者」之定義問題。因此，吾人需要一種科學化、定量且快速診斷複合性基因疾病之方法。 1228980 A7 五、發明説明（4 ) ^ --一一發明概述本發明之目的在提供建立診斷及/或預判一個體之複合性基因疾病指數之方法，其包括下列步驟· ⑷在該個體巾測量料擇與該複合性基因疾病有關之一個以上之基因之表現值； (b)使用-關係式計算該表現值而得—指數，該指數代表琢個體罹患該複合性基因疾病之機率及/或嚴其中步驟(b)之關係式係由包含下列步驟之方法而得： (i)藉病歷史、身體檢查、試驗檢測及放射線診斷以評估一群患有該複合性基因疾病之病患之病況評分 (condition scores)； (⑴測量該等病患就經選擇與該複合性基因疾病有關之基因之表現值；及、（111)將步驟⑴及（u)所得病患之病況評分與基因表現值進行統計學分析及迴歸處理而得該關係式。本發明又一目的在於提供建立診斷及/或預判一個體之氣喘指數之方法，其包括下列步驟： (a) 在該個體中測量經選擇與氣喘有關之一個以上之基因之表現值； (b) 使用一關係式計算該表現值而得一氣喘指數，該氣喘指數代表該個體罹患氣喘之機率及/或嚴重性；其中步驟（b)之關係式係由包含下列步驟之方法而得： (1)藉病歷史、身體檢查、試驗檢測及放射線診斷以評估一群患有氣喘之病患之病況評分； -------- - 7 - 本紙張尺度itifl中國國家標準(CNS) A4氣格(2i〇xl^公董)------- 1228980Line 1228980 A7 B7 V. Description of the invention (3) The patient describes the symptoms in different ways, and sometimes the doctor cannot make a correct diagnosis. Some studies have attempted to diagnose complex genetic diseases based on genetic analysis (Quinzii C et al., Predictive genetic testing-new possibilities in determination of risk of complex diseases. CMJ, 200 1; 42 (4): 45 8- 462; Joos L and Stanford AJ, Genotype predictors of response to asthma medications. Current opinion in pulmonary medicine 2002; 8: 9-15; Brutsche MH et al., Array-based diagnostic gene-expression score for atopy and asthma. J allergy Clin Immunol 2002; 1 09:27 1-273, Sheppard D, Uses of expression microarrays in studies of pulmonary fibrosis, asthma, cute lung injury, and emphysema. Chest 2002, 121 (Sup3): 21S-25S). However, these studies have focused on a few genes related to complex genetic diseases, and none have revealed the association of multiple genes. Brutsche MH et al. Provided a scoring index called the Composite Atopy Gene Expression (CAGE) index for diagnosis of allergies and asthma. The CAGE index means the overall difference in the performance of 10 genes between patients and "healthy people." However, the CAGE index is not a good diagnostic indicator. This is because genes with different functions provide different degrees of function. In addition, there are also problems with the definition of "healthy". Therefore, we need a scientific, quantitative and rapid method for diagnosing complex genetic diseases. 1228980 A7 V. Description of the invention (4) ^-Summary of the invention The purpose of the present invention is to provide a method for establishing a diagnosis and / or predicting a compound genetic disease index of an individual, which includes the following steps: Measure the performance value of one or more genes related to the complex genetic disease; (b) use the -relational formula to calculate the performance value-an index, which represents the probability of the individual suffering from the complex genetic disease and / Or the relational expression of step (b) is obtained by a method including the following steps: (i) Evaluating the condition of a group of patients with the complex genetic disease through medical history, physical examination, test and radiation diagnosis Condition scores; (⑴ measure the performance values of these patients in selecting genes associated with the complex genetic disease; and (111) condition scores and gene performance of the patients obtained in steps (i) and (u) The relationship is obtained by statistical analysis and regression processing. Another object of the present invention is to provide a method for establishing a diagnosis and / or predicting a person's asthma index, which includes the following steps: (a ) Measure the performance value of one or more genes selected for asthma in the individual; (b) calculate the performance value using a relationship to obtain an asthma index, which represents the individual's chance of developing asthma and / or Severity; where the relational expression of step (b) is obtained by a method comprising the following steps: (1) Evaluation of the condition score of a group of patients with asthma by medical history, physical examination, test and radiation diagnosis;- --------7-This paper size itifl Chinese National Standard (CNS) A4 gas grid (2i〇xl ^ public director) ------- 1228980

(ϋ) 值；及 /則I邊等病患就經選擇與氣喘有關之基因之表現㈤）將步驟⑴及（U)所得病患之病況評分及基::叶學分析及迴歸處理而得該關係式。 2發月k供建互診斷及/或預判—個體之複合性基因疾病扣數<方法，其包括下列步驟： ⑷在該個體中測量經選擇與該複合性基因疾病有關之一個以上之基因之表現值；=)使用_關係式計算該表現值而得—指數，該指數代 X個to罹患咸複合性基因疾病之機率及/或嚴重性；其中步驟(b)之關係式係由包含下列步驟之方法而得： (I) 藉病歷史、身體檢查、試驗檢測及放射線診斷以評估一群患有^複合性基因疾病之病患之病況評分； (II) /則f孩等病患就經選擇與該複合性基因疾病有關之基因之表現值；及.(ϋ) value; and / or I, the performance of patients selected by asthma-related genes on the basis of ㈤) The score and basis of the condition of the patient obtained in step ⑴ and (U) :: Yeast analysis and regression processing The relationship. 2 months for mutual diagnosis and / or prejudgment—the number of individuals with a compound genetic disease < method, which includes the following steps: 测量 measuring in the individual one or more of the genes selected to be related to the compound genetic disease The expression value of the gene; =) The index is calculated by using the _ relation to calculate the expression value, the index represents the probability and / or severity of the X to suffer from the salty complex gene disease; wherein the relationship of step (b) is given by It is obtained by a method including the following steps: (I) assessing the condition score of a group of patients with a complex genetic disease by using medical history, physical examination, laboratory tests and radiological diagnosis; (II) / f The performance values of genes selected for the complex genetic disease; and

*裝訂 ("1)將步風（1)及（i i)所得病患之病況評分與基因表現值進行統計學分析及迴歸處理而得該關係式。本文所p之複合性基因疾病」一詞亦稱為多因素疾病，代表與多重基因、非基因因素及多重基因、以及非基因因素間交互作用有關之疾病。複合性基因疾病—般具有多種型態之病徵且常被誤認為其他疾病。該複合性基因疾病包含（但不限於）氣喘、第一型糖尿病、風濕性關節炎、紅斑性狼瘡、椎骨粘黏、牛皮癖或精神***症。本發明之本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱)* Binding (" 1) Statistical analysis and regression analysis of the patient's condition scores and gene expression values obtained from the steps (1) and (i i) to obtain the relationship. The term "complex genetic disease" as used herein is also referred to as multifactorial disease, and represents diseases related to the interaction between multiple genes, nongenetic factors and multiple genes, and nongenetic factors. Complex genetic disease—Symptoms of multiple types are common and often mistaken for other diseases. The composite genetic disease includes, but is not limited to, asthma, type 1 diabetes, rheumatoid arthritis, lupus erythematosus, vertebral stickiness, psoriasis, or schizophrenia. The paper size of the present invention is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 public love)

12289801228980

較佳具體例中，該複合性基因疾病為氣喘或風濕性關節炎。本發明之最佳具體例為氣喘。本又所言之「指數」意指一表示個體罹患疾病或病況之機率及/或嚴重性之數值。本文所言之「病況評分」—詞代 =用以診斷及/或預判複合性基因疾病之一準則、一些準則或其組合，例如病患感受之病徵、醫師所作之症狀檢視、實^«數據放射學發現及/或家族病歷史、有數據結合顯示之病歷史、身體檢查、試驗檢測或放射線診斷。用以診斷複合性基因疾病之任何已建立或新界定之病況評分均可用於本發明。本發明較佳具體例中，代表综合評估氣喘嚴重性之氣喘評分、代表病患服藥次數之醫藥評分、代表病患服用類固醇藥物次數之類固醇評分、丨秒内用力呼氣量 (FEV,)、高峰呼氣流量（PEFR)、用力肺活量（fvc)、邮量、對抗原特異之IgE、嗜伊紅血球及嗜伊紅性血球陽離子蛋白質（ECP)量均可使用作為診斷氣喘之病況評分。本文利之「經選擇與複合性基因疾病有關之基因」代表被證明或被假設與複合性基因疾病有關之基因或基因群。該等基因包含(但不限於)直接或間接調節細胞表現(其與複合性基因疾病有關）之活化及/或退化之基因，及可編碼直接或間接控制所有生理反應（包含内在維持及對外在改變之反應)蛋白質之基因’較佳是有多於一個以上經選擇盘複合性基因疾病有關之基因。例如，經選擇與氣喘有關之基因為編碼細胞素之基因、編碼受體之基因、編碼轉錄因子之基因、編碼發訊分子之基因、編碼化學增活素之基本纸張尺度適用中國國家標準(CNS) A4$格(210X297公复----—- _ 1228980 五、發明説明（，因、編碼黏著分子之基因或其組合。 =據=明’經選擇與複合性基因疾病有關之基因表現基因晶片或聚合酶鏈反應（PCR)測量。可用以測量二表:見疋樣品包括取自個體之血液、血清、細胞或組織，較佳為血液樣品。該基因表現可在嚴格條件下，經触人驗基互補之標的聚核芬酸雜交而測量。本發明較佳具 t例中，多重標的聚核菩酸係以微陣列放置在—固體或一 ri上’並以單—步驟進行多重基因表現之測量。此技藝中慣用之任何基目表現測量料均可科本發明。 /依據本發明’該關係式係對病患之病況評分及表現值進 :統计學分析而後之迴歸處理而得。本發明較佳具體例，統計學分析及迴歸處理為皮耳森相關（Pearson Γ_η°η)及多重線性迴歸方式，其可經已商業化之程式（如SPSS)進行。本發明之診斷精確性係視所選擇之基因、病患數及多樣 2而異：其中之病患是指被收集病況評分而得關係式之個月且較佳是儘可能選擇較多之基因。然而，並非所有基因均與複合性基因疾病有關。經收集病況評分而得關係式《病患數亦將影響該精確性’理論上，診斷精確性隨病患數增加而增加。依據本發明，由於病患之多樣性，因此，不同病患群將可得不同之關係式，該病患群可藉性別'年齡及/或生活環境分類。依據本發明，醫師可就一疑似罹患該複合性基因疾病之個體得到-指數’用以快速且客觀地判斷該個體是否患有本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公憂) -10 1228980 A7 五、發明説明^ ---*----- 8 4複合性基因疾病、疾病嚴重度及如何用藥。、依據本發明可提供建立診斷及/或預判-個體之氣端指數 <万法，其包括下列步驟： ⑷在該個體中測量經選擇與該氣喘有關之一個以上之基因之表現值； ☆⑻使用-關係式計算該表現值而得—氣喘指數，該氣 %指數代表該個體罹患氣喘之機率及/或嚴重性；其中步驟（b)之關係式係由包含下列步驟之方法而得： (1)藉病歷史、身體檢查、試驗檢測及放射線診斷以評估一群患有氣喘之病患之病況評分； (U)檢測該等病患就經選擇與氣喘有關之基因之表現值；及 (in)將步驟（i)及（ii)所得病患之病況評分及基因表現值進行統計學分析及迴歸處理而得該關係式。下列實例僅作為說明之用途而並非用以限制本發明範圍。實例复土匕1 :診斷氣喘之關係< 病患：以下列標準選擇出患有因塵蟎引起過敏性氣喘之5 2位病患：（1)血清中IgE總量升高（高於100ku/毫升）；皮膚試驗中對一般過敏原呈陽性反應；（3 )血清中對C AP特異之IgE量升高（高於2ku/毫升）；及（4)吸入支氣管擴張劑後肺功能可逆升高達1 5 %。 _____-11- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）In a preferred embodiment, the complex genetic disease is asthma or rheumatoid arthritis. A preferred embodiment of the present invention is asthma. As used herein, "index" means a numerical value that indicates the probability and / or severity of an individual's disease or condition. The "condition score" referred to in this article-word generation = one of the criteria for diagnosing and / or predicting a complex genetic disease, some criteria, or a combination thereof, such as the symptoms of the patient's feelings, the physician's symptom review, and the actual ^ « Data radiological findings and / or family disease history, medical history with data display, physical examination, laboratory tests or radiological diagnosis. Any established or newly defined condition score used to diagnose a complex genetic disease can be used in the present invention. In a preferred embodiment of the present invention, an asthma score representing a comprehensive assessment of the severity of asthma, a medical score representing the number of medications taken by a patient, a steroid score representing the number of times a patient takes a steroid, a forced expiratory volume within a second (FEV,), Peak expiratory flow (PEFR), forced vital capacity (fvc), postal volume, antigen-specific IgE, eosinophils, and eosinophilic cationic proteins (ECP) can all be used as diagnostic scores for asthma. The “genes selected for a complex genetic disease” in this article represent genes or gene groups that have been proven or hypothesized to be related to a complex genetic disease. These genes include (but are not limited to) genes that directly or indirectly activate and / or degrade cellular performance (which is associated with complex genetic diseases), and can encode direct or indirect control of all physiological responses, including internal maintenance and external Altered response) The gene of the protein is preferably more than one gene associated with a selected disc complex gene disease. For example, the basic paper size of asthma-related genes selected is the gene encoding cytokines, the gene encoding receptors, the gene encoding transcription factors, the gene encoding signaling molecules, and the basic paper size encoding chemical activators. CNS) A4 $ lattice (210X297 public reply ---- — _ 1228980) V. Description of the invention (, cause, gene encoding adhesive molecules or a combination thereof. = Data = Ming 'selected gene expression related to complex genetic diseases Gene chip or polymerase chain reaction (PCR) measurement. It can be used to measure two tables: see the sample includes blood, serum, cells or tissues taken from an individual, preferably a blood sample. The gene performance can be determined under stringent conditions, by The measurement is performed by hybridization of a target polynuclear acid that is complementary to a human test base. In the present invention, preferably, the multi-target polynuclear acid is placed in a microarray on a solid or a ri 'and multiplexed in a single step. Gene expression measurement. Any subject performance measurement material commonly used in this technique can be used in the present invention. / According to the present invention, the 'relationship' is used to evaluate the patient's condition score and performance values: statistical analysis and then It is obtained by regression processing. The preferred specific example of the present invention is statistical analysis and regression processing using Pearson correlation (Pearson Γ_η ° η) and multiple linear regression methods, which can be performed by commercialized programs (such as SPSS). The diagnostic accuracy of the invention varies depending on the selected gene, the number of patients, and the diversity2: the patient refers to the month that is obtained by collecting the condition scores and the relationship is preferably as many genes as possible. However, not all genes are related to a complex genetic disease. The relationship "the number of patients will also affect the accuracy" obtained by collecting condition scores. In theory, the accuracy of diagnosis increases with the number of patients. According to the present invention, Due to the diversity of patients, different relationships will be obtained for different patient groups, and the patient groups can be classified by gender 'age and / or living environment. According to the present invention, a physician can suspect that the compound Individuals with genetic disease-indexes are used to quickly and objectively determine whether the individual has this paper. Applicable to China Paper Standard (CNS) A4 (210 X 297 public concern) -10 1228980 A7 Explanation ^ --- * ----- 8 4 Complex genetic diseases, disease severity and how to use drugs. According to the present invention, it can provide the establishment of diagnosis and / or prejudgment-individual air end index < wanfa, which It includes the following steps: 测量 Measure the performance value of one or more genes selected for the asthma in the individual; ☆ ⑻ Calculate the performance value using the -relational formula-asthma index, the qi% index represents the individual suffering from asthma Probability and / or severity; where the relationship of step (b) is derived from a method that includes the following steps: (1) Evaluation of a group of patients with asthma by medical history, physical examination, laboratory testing, and radiological diagnosis Condition scores; (U) testing the patient's performance values for selected genes related to asthma; and (in) statistically analyzing the condition scores and gene performance values of the patients obtained in steps (i) and (ii) The relationship is obtained by analysis and regression processing. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Example Compound soil 1: Diagnosing the relationship between asthma < Patients: 5 patients with allergic asthma caused by dust mites were selected according to the following criteria: (1) the total amount of IgE in serum was increased (greater than 100ku) / Ml); positive response to general allergens in skin tests; (3) increased serum AP-specific IgE (greater than 2ku / ml) in serum; and (4) reversible increase in lung function after inhalation of bronchodilators Up to 15%. _____- 11- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

A7 B7 1228980 五、發明説明（f &喘病況評合評色·· 、患有氣％足病患經醫師參考病歷史、身體檢查及試驗檢測加以鑑足。下列用於診斷病患氣喘之病況評分係依據上述數據評估：氣喘評分、醫藥評分，固醇評分、1秒内用力啤氣量（FEVl)、高峰呼氣流量（pEFR)、用力肺活量 (FVC) IgE量、對抗原特異之IgE、_伊紅血球及嗓伊紅性血球陽離子蛋白質（E c p)量。核甞酸檨品夕：自病患體採取血樣並置於含EDTA之試管中，接著在 2,5〇〇rpm離心2〇分鐘，並分離出含白血球細胞層。在含白血球層中添加無菌磷酸鹽緩衝液（pBs)以清洗白血球，接著再以1，500 rpm離心1〇分鐘2次，接著在 4,〇〇〇g及4°C離心15分鐘後收集細胞。再於細胞内添加 1毫升TRIZOL試劑並藉聲振器打破細胞。離心後，將所得細胞與0.2毫升CHC13混合並再度聲振。在於 14,000g離心15.分鐘以分離RNA及細胞粒，並於含 RNA足分液中添加5 0 0微升異丙醇且混合之。所得混合物在-2(TC維持約20分鐘。在4°C，藉1 4,000g離心15分鐘以移除混合物中之粒片。經乙醇沉澱後，將混合物中之 RNA落於不含RNA酶之水中以獲得聚核芬酸樣品，並許估 RNA 濃度（260nm/280nm)。標記基因標記：將8微升聚核甞酸樣品及2微升寡聚_dT(12_18聚體， 0.1微克/微升）充分混合並在70。(：維持1〇分鐘，接著以冰A7 B7 1228980 V. Description of the invention (f & asthma condition evaluation and evaluation ...), patients with Qi% foot disease will be referred to the doctor by referring to the history of the disease, physical examination and test detection. The following is used to diagnose the condition of asthma in patients The score is evaluated based on the above data: asthma score, medical score, sterol score, forced beer volume (FEVl), peak expiratory flow (pEFR), forced vital capacity (FVC) IgE, antigen-specific IgE, _ Amount of erythrocyte and erythrocytic cationic protein (E cp). Nucleic acid syrup: take a blood sample from the patient and place it in a test tube containing EDTA, then centrifuge at 2,500 rpm for 20 minutes, The white blood cell-containing layer was separated. The white blood cell-containing layer was added with sterile phosphate buffered saline (pBs) to wash the white blood cells, followed by centrifugation at 1,500 rpm twice for 10 minutes, and then at 4,000 g and 4 Cells were collected after centrifugation at 15 ° C. Then 1 ml of TRIZOL reagent was added to the cells and the cells were broken by a sonicator. After centrifugation, the resulting cells were mixed with 0.2 ml of CHC13 and sonicated again. Centrifuge at 14,000g for 15. Isolate RNA and fine 500 microliters of isopropanol were added to the RNA-containing foot solution and mixed. The resulting mixture was maintained at -2 ° C for about 20 minutes. At 4 ° C, centrifuged at 1 4,000 g for 15 minutes to remove Granules in the mixture. After ethanol precipitation, the RNA in the mixture was dropped into RNase-free water to obtain a polynuclear acid sample, and the RNA concentration (260nm / 280nm) was estimated. Labeled gene labeling: 8 micro 1 liter of polynucleic acid sample and 2 μl of oligo_dT (12-18 mer, 0.1 μg / μl) were thoroughly mixed and maintained at 70. (: maintained for 10 minutes, followed by ice

-裝訂-Binding

線line

12289801228980

塊冷卻2分鐘。所得聚核荅酸樣品與逆轉錄標記混合物在黑暗處混合並與3微升Cy5-dUTp(lmM)、2微升 SuperScrip Π(200υ/微升）及 Ransin(1 微升）混合。該混合物在42。(：培育2小時以進行反轉錄反應，並藉添加 1·5微升2〇mM EDTA終止反應。藉添加ι·5微升 50 0mM NaOH降解聚核:y：酸樣品並加熱1〇分鐘。接著藉添加1·5微升500mM HC1中和留在聚核荅酸樣品中之 NaOH ,並藉由ProbeQuant G_5〇微管柱中旋轉以移除過量之C y 5。以C y 5標記之所有聚核荅酸樣品均儲存於_ 2 〇 V。 ' 1的聚核#酸之劊備：所選擇之基因藉由聚合酶鏈反應擴增，接著溶於點墨 (spotting)緩衝液中作為標的聚核苷酸。在95t：變性3分鐘後，該標的聚核荅酸藉紫外線使用點墨機點著至玻璃載體上形成偵測基因表現用之晶片。播的聚核甞酸及樣品聚核諒酸間之相互反廄：藉N -甲基p比任利二酮（n-methyl-pyrilidione)/琥珀酸酐/硼酸鈉及5X SSC/0.1% SDS/1% BSA預處理含標的聚核甞酸之晶片以阻斷玻璃載體上之活性基而消除非特異雜交。以含於雜交緩衝液（50%甲醯胺/02〇/〇 sDS/10 X SSC)中之Cy5標記聚核:y：酸樣品，接著在95t：變性5分鐘並冷卻。將聚核：y：酸樣品負載至晶片上。標的聚核答酸及聚核菩酸樣品之雜交反應在4 2。(：進行1 8小時。使用3 種溶液（IX SSC/0.1% SDS、0.1X SSC/0.1% SDS 及 -13- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） 1228980 A7 B7 五、發明説明（u ) ο · 1X s s c)清洗樣品及移除對標的核：y：酸非特異之核甞酸或未雜交之核甞酸。訊號測量：使用螢光掃描器掃描晶片以偵測及分析基因表現，加以定量分析而得表現值。螢光訊號以 GenePixTM Pro3.0(Ax〇n儀器公司）定量分析，接著減去背景值，再除以管理基因（house keeping gene)GAPDH (甘油酸磷酸脫氫酶），並以小鼠cDNA(ATBS)及植物DNA(RbCL) 作為陰性對照組。分析: 各表現值為兩測值之平均。對氣喘之病況評分以及各經選擇基因之表現值進行皮耳森相關及多重線性迴歸處理，係以SPSS 8.0 1統計套裝程式完成。氣喘之各病況評分及各基因表現值之關聯性列於表1。表1 : 基因型氣喘評分 FEVj 類固醇評分 IgE 對Dp 特異之 IgE 嗜伊紅血球量 ECP -281 224 -212 '073 .029 •194 .181 ACHE (.006)** (.066)* (0.039)** (.490) (.780) (.064)* (.104) -.110 -217 .073 -.108 -.134 -.022 •023 CCR1 (289) (.076)* (.481) (.304) (201) (.838) (.837) _- 14- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1228980 A7 B7 五、發明説明（12 ) -.183 '197 •015 -.097 -.047 .088 .128 CD31 (.076)* (.107) (.885) (356) (.655) C405) (251) 集落刺激因-.039 -.022 '032 '159 '160 •014 •147 子3 (.707) (.859) (.757) (•129) (.126) (.893) (.188) .011 .100 -.155 .095 .028 .069 201 GBP1 (.919) (•419) (.134) (.367) (.793) (.511) (.071)* '178 •170 '021 •021 .109 .112 216 IL12受體β2 (.085)* (•167) (.843) (.846) (299) (•287). (.051)* -.105 •037 -.095 -.057 .011 •163 281 IL18受體 (•312) (.766) (357) (.591) (•914) (•121) (.011)** •082 .048 -.054 -.028 .040 253 •088 IRF4 (.427) (.699) (.602) (.793) (.706) (.015)** (•432) -276 .006 -•134 -.025 •014 •088 290 金屬碗*蛋白 (.007)** (.961) (•190) (.816) (.808) (.406) (.008)** ••019 •018 -.134 .027 .032 247 260 MUC2 (.065)* (.886) (•197) (•795) (.758) (.018)** (.019)** 229 282 -.001 -.180 -224 •186 -.042 SCYA4 (.026)** (.020)** (.991) (.087)* (.031)** (.076)* (.706) -.171 -.128 -.128 -.048 .024 •159 .081 STAT6 (.097)* (299) (217) (.649) (.031)** 0129) (.467) -.118 .048 -•159 .036 .009 233 •116 ACHE 一 2 0255) (.698) (•125) (.737) (•935) (.026)** (299) -.168 -.162 -.106 -.045 -•023 •076 .091 CCR3 C104) (.187) (.308) (.668) (.829) (•473) (.416) ____-15- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）The block was cooled for 2 minutes. The resulting polynucleotide sample was mixed with the reverse transcription labeling mixture in the dark and mixed with 3 µl of Cy5-dUTp (lmM), 2 µl of SuperScrip Π (200υ / µl), and Ransin (1 µl). The mixture is at 42. (: Incubate for 2 hours for reverse transcription reaction, and stop the reaction by adding 1.5 microliters of 20 mM EDTA. Degrade polynuclear: y: acid samples by adding 1.5 microliters of 50 mM NaOH and heat for 10 minutes. Then add 1.5 microliters of 500 mM HC1 to neutralize the NaOH remaining in the polynucleic acid sample, and spin the ProbeQuant G_50 microtube column to remove excess C y 5. All labeled with C y 5 Polynucleotide samples were stored at _20 volts. Preparation of Polynucleotide # 1: The selected gene was amplified by polymerase chain reaction and then dissolved in spotting buffer as the target Polynucleotide. After 95t: 3 minutes of denaturation, the target polynucleic acid was spotted on the glass carrier by ultraviolet light using an ink dispenser to form a wafer for detecting gene expression. Polynucleotide sowed and polynucleus of the sample Reciprocal reaction between acids: N-methyl p-n-methyl-pyrilidione / succinic anhydride / sodium borate and 5X SSC / 0.1% SDS / 1% BSA pretreatment with standard polynuclear The acidic wafer is used to block the active groups on the glass carrier to eliminate non-specific hybridization. It is contained in hybridization buffer (50% formamidine / 02〇 / 〇sDS / 10). X SSC) Cy5 labeled polynuclear: y: acid sample, then denatured at 95t: 5 minutes and cooled. Load polynuclear: y: acid sample on the wafer. The target polynuclear acid and polynuclear acid sample The hybridization reaction was performed at 42. (: 18 hours. Use 3 kinds of solutions (IX SSC / 0.1% SDS, 0.1X SSC / 0.1% SDS and -13- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love) 1228980 A7 B7 V. Description of the invention (u) ο · 1X ssc) Wash the sample and remove the target nucleus: y: non-specific nucleic acid or unhybridized nucleic acid. Signal measurement: use A fluorescence scanner scans the chip to detect and analyze gene expression, and quantitatively obtains the expression value. The fluorescence signal is quantitatively analyzed with GenePixTM Pro3.0 (Axon Instrument Co., Ltd.), and then the background value is subtracted and divided by the management Gene (house keeping gene) GAPDH (glycerate phosphate dehydrogenase), and mouse cDNA (ATBS) and plant DNA (RbCL) as negative control group. Analysis: Each performance value is the average of two measurements. For asthma Pearson correlation and multiplicity of condition scores and performance values of selected genes The sexual regression processing was completed with the SPSS 8.0 1 statistical package program. The correlation between the asthma condition scores and the gene expression values is shown in Table 1. Table 1: Genotype asthma score FEVj Steroid score IgE Dp-specific IgE Addiction Red blood cell volume ECP -281 224 -212 '073 .029 • 194 .181 ACHE (.006) ** (.066) * (0.039) ** (.490) (.780) (.064) * (.104) -.110 -217 .073 -.108 -.134 -.022 • 023 CCR1 (289) (.076) * (.481) (.304) (201) (.838) (.837) _- 14- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 1228980 A7 B7 V. Description of the invention (12) -.183 '197 • 015 -.097 -.047 .088 .128 CD31 (.076 ) * (.107) (.885) (356) (.655) C405) (251) Colony stimulation factor -.039 -.022 '032' 159 '160 • 014 • 147 Sub 3 (.707) (.859) ) (.757) (• 129) (.126) (.893) (.188) .011 .100 -.155 .095 .028 .069 201 GBP1 (.919) (• 419) (.134) (.134) 367) (.793) (.511) (.071) * '178 • 170' 021 • 021 .109 .112 216 IL12 receptor β2 (.085) * (• 167) (.843) (.846) ( 299) (• 287). (.051) * -.105 • 037 -.095 -.05 7 .011 • 163 281 IL18 receptor (• 312) (.766) (357) (.591) (• 914) (• 121) (.011) ** • 082 .048 -.054 -.028 .040 253 • 088 IRF4 (.427) (.699) (.602) (.793) (.706) (.015) ** (• 432) -276 .006-• 134 -.025 • 014 • 088 290 Metal Bowl * protein (.007) ** (.961) (• 190) (.816) (.808) (.406) (.008) ** •• 019 • 018 -.134 .027 .032 247 260 MUC2 (.065) * (.886) (• 197) (• 795) (.758) (.018) ** (.019) ** 229 282 -.001 -.180 -224 • 186 -.042 SCYA4 ( .026) ** (.020) ** (.991) (.087) * (.031) ** (.076) * (.706) -.171 -.128 -.128 -.048 .024 • 159 .081 STAT6 (.097) * (299) (217) (.649) (.031) ** 0129) (.467) -.118 .048-• 159 .036 .009 233 • 116 ACHE 1 2 0255 ) (.698) (• 125) (.737) (• 935) (.026) ** (299) -.168 -.162 -.106 -.045-• 023 • 076 .091 CCR3 C104) (. 187) (.308) (.668) (.829) (• 473) (.416) ____- 15- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

•裝訂• Binding

1228980 A7 B7 五、發明説明 (13 ) CD34 '020 '039 .080 '097 '116 .048 201 (.851) (.749) (.443) (.359) (270) (.650) (.071)* CXCR3 -.004 •174 .004 .023 '032 •158 .082 (GPR9) (.967) (•155) (.972) (.828) (.760) (•132) (.463) GBP2 240 242 '029 -.031 '111 .144 '001 (.019)** (.046)** (.782) (.768) (289) (.172) (•991) 112 受體 β-.3〇9 .093 -214 .014 •055 •180 .040 22 (.002)** (.451) (.037)** (.894) (.602) (.086)* (.722) IL4 •174 214 .005 -.098 -.190 •191 •051 (.092)* (.080)* (.963) (.355) (.068)* (.068)* (.649) IRF4一2 -286 '101 '178 .102 .106 •165 •125 (.005)** _ (.085)* (335) (•312) (.117) (265) 金屬硫蛋白-.385 '114 -238 .096 .061 •107 246 一2 (.000)** (.355) (.020)** (.362) (.559) (310) (.026)** MUC5AC '110 '145 '077 '023 -.068 236 258 (289) (236) (•457) (.875) (•516) (.023)** (.019)** 選擇素-266 .061 '337 .038 •116 •156 •183 selectin)L (.009)** (.620) (.001)** P16) (267). (•138) (•101) TBXA2R '053 '088 '114 .056 .006 .092 259 (•611) (.474) (271) (•593) (.955) (.382) (.019)** 腺甞酸環化.171 •137 •053 '180 '180 •032 -.121 酶1 (.098)* (266) (.611) (.086)* (.085)* (209) (277) CCR5 -243 '088 -.055 -.062 -.001 229 •143 (.018)** (.477) (.595) (•554) (.990) (.028)** (200) -16- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）1228980 A7 B7 V. Description of the invention (13) CD34 '020' 039 .080 '097' 116 .048 201 (.851) (.749) (.443) (.359) (270) (.650) (.071 ) * CXCR3 -.004 • 174 .004 .023 '032 • 158 .082 (GPR9) (.967) (• 155) (.972) (.828) (.760) (• 132) (.463) GBP2 240 242 '029 -.031' 111 .144 '001 (.019) ** (.046) ** (.782) (.768) (289) (.172) (• 991) 112 receptor β-. 3〇9 .093 -214 .014 • 055 • 180 .040 22 (.002) ** (.451) (.037) ** (.894) (.602) (.086) * (.722) IL4 • 174 214 .005 -.098 -.190 • 191 • 051 (.092) * (.080) * (.963) (.355) (.068) * (.068) * (.649) IRF4-1 2 -286 '101' 178 .102 .106 • 165 • 125 (.005) ** _ (.085) * (335) (• 312) (.117) (265) metallothionein-.385 '114 -238 .096 .061 • 107 246-2 (.000) ** (.355) (.020) ** (.362) (.559) (310) (.026) ** MUC5AC '110' 145 '077' 023 -.068 236 258 (289) (236) (• 457) (.875) (• 516) (.023) ** (.019) ** Selectin -266 .061 '337 .038 • 116 • 156 • 183 selectin) L (.009) ** (.620) (.001) ** P16) (267). (• 138) (• 101) TBXA2R '053' 0 88 '114 .056 .006 .092 259 (• 611) (.474) (271) (• 593) (.955) (.382) (.019) ** Adenylate cyclization. 171 • 137 • 053 '180' 180 • 032 -.121 enzyme 1 (.098) * (266) (.611) (.086) * (.085) * (209) (277) CCR5 -243 '088 -.055 -.062 -.001 229 • 143 (.018) ** (.477) (.595) (• 554) (.990) (.028) ** (200) -16- This paper size applies Chinese National Standard (CNS) A4 size (210 X 297 mm)

1228980 A7 B7 五、發明説明 (14 ) -210 -.047 -.066 .042 .028 •116 •030 CD38 (.041)** (•705) (.525) (.692) (.792) 〇269) (•791) '058 -.131 -.055 '015 -.096 •035 .048 EGR2 (.575) (286) (•595) (.888) (.360) (.739) (.666) -.146 .014 '054 -.022 -.081 .067 206 HOXA1 (.157) (•913) (.602) (.838) (•441) (.523) (.043)** 麵295 .056 -244 229 •155 .190 '051 IL13 (.004)** (.650) (.017)** (.028)** (.138) (.069)* (.647) '476 -.017 -.112 •026 .046 •167 .190 IL4受體α (.000)** (.891) (282) (.802) (.664) (.111) (.087)* '108 .053 -208 .082 .017 .078 .155 UGA6 (296) (•674) (.043)** C436) (.868) (.460) (.164) .171 250 -.025 -.042 '114 266 •011 金屬石瓦蛋白 (.098)* (.040)** (.809) (.682) (278) (.010)** (.920) '074 -.176 '158 .009 .000 •129 290 PDE4B (.476) (.150) (.125) (.935) (.998) C219) (.008)** -214 '149 -.194 .093 .025 •112 .104 SLAM (.037)** (225) (.059)* (.378) (.815) (288) (.352) 202 268 '019 -.108 -.166 201 -.024 TBXA2R2 (.050)** (.027)** (.854) (.305) C1H) (.054)* (.827) 腺甞酸環化-.123 -.013 -202 '066 -.033 .344 246 酶1 一2 (234) (•919) (.050)** (•535) (.756) (.001)** (.026)** '380 -.034 -261 •139 .160 256 •169 CCR7 (.000)** (.782) (.011)** (.186) -17- (.126) (.014)** (.128) 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）1228980 A7 B7 V. Description of the invention (14) -210 -.047 -.066 .042 .028 • 116 • 030 CD38 (.041) ** (• 705) (.525) (.692) (.792) 〇 269) (• 791) '058 -.131 -.055' 015 -.096 • 035 .048 EGR2 (.575) (286) (• 595) (.888) (.360) (.739) (.666 ) -.146 .014 '054 -.022 -.081 .067 206 HOXA1 (.157) (• 913) (.602) (.838) (• 441) (.523) (.043) ** surface 295 .056 -244 229 • 155 .190 '051 IL13 (.004) ** (.650) (.017) ** (.028) ** (.138) (.069) * (.647)' 476- .017 -.112 • 026 .046 • 167 .190 IL4 receptor alpha (.000) ** (.891) (282) (.802) (.664) (.111) (.087) * '108. 053 -208 .082 .017 .078 .155 UGA6 (296) (• 674) (.043) ** C436) (.868) (.460) (.164) .171 250 -.025 -.042 '114 266 • 011 Metal Lithoprotein (.098) * (.040) ** (.809) (.682) (278) (.010) ** (.920) '074 -.176' 158 .009 .000 • 129 290 PDE4B (.476) (.150) (.125) (.935) (.998) C219) (.008) ** -214 '149 -.194 .093 .025 • 112 .104 SLAM (. 037) ** (225) (.059) * (.378) (.815) (288) (.352) 202 268 '019 -.108 -.16 6 201 -.024 TBXA2R2 (.050) ** (.027) ** (.854) (.305) C1H) (.054) * (.827) adenylate cyclization -.123 -.013 -202 '066 -.033 .344 246 Enzyme 1-2 (234) (• 919) (.050) ** (• 535) (.756) (.001) ** (.026) **' 380 -.034 -261 • 139 .160 256 • 169 CCR7 (.000) ** (.782) (.011) ** (.186) -17- (.126) (.014) ** (.128) This paper size Applicable to China National Standard (CNS) A4 (210 x 297 mm)

-裝-Load

1228980 A7 B7 五、發明説明（15 ) -.039 •147 .104 •051 .055 234 .158 CD69 (.709) (230) (.314) (.632) (.600) (.025)** (.155) -.050 •055 -.001 -.089 -.112 •079 -.014 Eotaxin (.631) (.658) (.991) (.398) (285) (.456) (.897) '114 •020 '117 -.172 -.160 .040 •198 HOXA1 2 (272) (.873) (258) (•102) (.120) (.705) (.074)* .312 .137 .017 -•055 '099 .119 -.017 IL15 (.002)** (264) (.872) (.603) (346) (•259) (.879) ••194 -.052 -238 .044 -.036 .073 .190 IL5受體α (.060)* (.675) (.020)** (.678) (.733) (.488) (.087)* '409 •108 -.306 •016 .033 .140 •088 UGB7 (.000)** (379) (.003)** (.881) (.754) (•182) (•430) -•101 -.023 -.066 -.067 -.014 •150 287 MG (330) (.851) (.526) (•527) (.896) (.155) (.009)** 211 •077 .001 -.102 -.114 213 .005 PDPK (.006)** (•534) (.995) (334) (279) (.041)** (.967) -294 -.063 -269 •134 •145 •185 •126 STAT1 (.004)** (•611) (.008)** (204) (.105) (.078)* (218) -.044 -.034 •017 -.011 -.028 .052 •172 TBXA2R3 (.670) C781) (.872) (.915) (.790) (.623) C123) 腺荅酸環化287 .066 .109 '120 '145 .141 •014 酶1 一3 (.005)** (•591) (292) (254) (.165) (.180) (.900) CD2 .140 284 '016 -.183 '171 .173 •020 (.175) (.019) (.881) (.082)* -18- (•101) (.099)* (.860) 本紙張尺度適用中國國家標準(CNs) A4規格(210X 297公釐）1228980 A7 B7 V. Description of the invention (15) -.039 • 147.104 • 051 .055 234 .158 CD69 (.709) (230) (.314) (.632) (.600) (.025) ** (.155) -.050 • 055 -.001 -.089 -.112 • 079 -.014 Eotaxin (.631) (.658) (.991) (.398) (285) (.456) (.897) ) '114 • 020' 117 -.172 -.160 .040 • 198 HOXA1 2 (272) (.873) (258) (• 102) (.120) (.705) (.074) * .312 .137 .017-• 055 '099 .119 -.017 IL15 (.002) ** (264) (.872) (.603) (346) (• 259) (.879) •• 194 -.052 -238. 044 -.036 .073 .190 IL5 receptor α (.060) * (.675) (.020) ** (.678) (.733) (.488) (.087) * '409 • 108-. 306 • 016 .033 .140 • 088 UGB7 (.000) ** (379) (.003) ** (.881) (.754) (• 182) (• 430)-• 101 -.023 -.066 -.067 -.014 • 150 287 MG (330) (.851) (.526) (• 527) (.896) (.155) (.009) ** 211 • 077 .001 -.102 -.114 213 .005 PDPK (.006) ** (• 534) (.995) (334) (279) (.041) ** (.967) -294 -.063 -269 • 134 • 145 • 185 • 126 STAT1 (.004) ** (• 611) (.008) ** (204) (.105) (.078) * (218) -.044 -.034 • 017 -.011 -.028 .052 • 172 TBXA2R3 (.670) C781) (.872) (.915) (.790) (.623) C123) Adenylate cyclization 287 .066 .109 '120' 145 .141 • 014 Enzyme 1-3 (.005) ** (• 591) (292) (254) (.165) (.180) (.900) CD2 .140 284 '016 -.183' 171 .173 • 020 (.175) (.019) (.881) (.082) * -18- (• 101) (.099) * (.860) This paper size applies to Chinese National Standards (CNs) A4 specifications (210X 297 Mm)

-裝-Load

1228980 訂1228980 Order

A7 B7 五、發明説明（16 ) '010 •153 •038 .062 .024 211 .055 \AJhil (.925) 〇213) (716) (•558) (.822) (.044)** (.627) •039 '075 '028 '140 -.043 •082 •113 ETS1 (711) (•544) (.785) (.182) (.084)* (.436) (313) '098 輯207 '064 -.041 -.066 •122 •088 ICAM1 (346) (.091)* (.540) (.701) (.528) (248) (.431) '056 '170 •017 '056 -.032 .070 233 BL15 2 (•587) (.166) (.872) (•598) (.758) (.505) (.035)** '196 •149 '088 •076 .030 .074 •307 IL5受體α 2 (.057)* (226) (.395) (.472) (.772) (.483) (.005)** '346 .190 -.172 •156 .172 239 216 LAMR1 (.001)** (•121) (.096)* 0137) (.098)* (.022)** (.051) '032 '059 .070 -.106 -.067 .191 •115 MUC1 (•761) (.632) (.500) (•315) C522) (.069)* (.302) .048 '077 .091 .051 -.058 •115 211 PRKG1 (.646) (.533) (.382) (.632) (.582) (276) (.053)* '085 '022 ••050 -.133 •119 •112 .015 STAT2 0412) (.861) (.632) (207) (255) (289) (.892) -.071 -.025 -.045 .063 .047 .098 .115 終端轉移S每 (.495) (.840) (.663) (•552) (.653) (.353) (.304) -.157 '054 -•035 -.131 -.100 .020 275 ADRB2 (.130) (.660) (.738) (314) (•853) (.012)** '070 -.038 .044 -.117 -.132 .109 221 CD26 (.501) (.756) (•673) C269) -19- (208) (.300) (.046)** 裝本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1228980 A7 B7 五、發明説明（17 ) -227 .131 '087 '034 '032 •139 •111 CDH3 (.027)** (288) (.401) (.750) (.760) (.185) (.320) ETS1 一2 •026 '013 -.052 .021 '148 '016 257 (.801) (.916) (.615) (.841) (•157) (.881) (.020)** -.403 •111 -247 .099 •051 '027 .104 ICAM2 (.000)** (369) (.016)** (347) (.630) (.798) (354) 255 .372 .049 '074 '174 202 •165 Π15 3 (.013)** (.000)** (.636) (.484) (.095)* (.053)* (•139) -.100 '013 .024 .047 •133 .108 .106 Π5受體α3 淋巴緩肽素β (•334) 1 (•914) (•817) (.655) (203) (.305) (.342) •074 -.012 -.045 .030 .035 •051 .109 (Lynphotactin beta) (.485) (•924) (.665) (•774) (203) (.627) (.330) -238 -.050 -.091 .066 .084 .173 212 MUC2 2 (.020)** (.083)* (•381) (•534) (•425) (.100) (.007)** •020 -238 .064 -.104 -•185 •045 293 PTGER2 (.846) (.050)** (.537) (323) (.076)* (•672) (.007)** -.122 -.057 -.061 .046 .060 •137 255 STAT4 (239) (.646) (.560) (.664) (.569) (.192) (.021)** -206 -.035 -.130 -.056 -.062 -.026 209 醛脫氫酶1 (.045)** (.780) (•593) (.553) (.809) (.059)* -.199 -.070 -239 -.073 .009 •135 .059 CD30 (.053)* (•572) (.020)** (.488) (.933) (200) (.599)A7 B7 V. Description of the invention (16) '010 • 153 • 038 .062 .024 211 .055 \ AJhil (.925) 〇213) (716) (• 558) (.822) (.044) ** (. 627) • 039 '075' 028 '140 -.043 • 082 • 113 ETS1 (711) (• 544) (.785) (.182) (.084) * (.436) (313)' 098 Series 207 ' 064 -.041 -.066 • 122 • 088 ICAM1 (346) (.091) * (.540) (.701) (.528) (248) (.431) '056' 170 • 017 '056 -.032 .070 233 BL15 2 (• 587) (.166) (.872) (• 598) (.758) (.505) (.035) ** '196 • 149' 088 • 076 .030 .074 • 307 IL5 Receptor α 2 (.057) * (226) (.395) (.472) (.772) (.483) (.005) ** '346 .190 -.172 • 156 .172 239 216 LAMR1 (. 001) ** (• 121) (.096) * 0137) (.098) * (.022) ** (.051) '032' 059 .070 -.106 -.067 .191 • 115 MUC1 (• 761 ) (.632) (.500) (• 315) C522) (.069) * (.302) .048 '077 .091 .051 -.058 • 115 211 PRKG1 (.646) (.533) (.382 ) (.632) (.582) (276) (.053) * '085' 022 •• 050 -.133 • 119 • 112 .015 STAT2 0412) (.861) (.632) (207) (255) (289) (.892) -.071 -.025 -.045 .063 .047 .098 .115 Terminal transfer S per (.495) (.840) (.663) (• 552) (.653) (.353) (.304) -.157 '054-• 035 -.131 -.100 .020 275 ADRB2 (.130) (.660) (.738) (314) (• 853) (.012) ** '070 -.038 .044 -.117 -.132 .109 221 CD26 (.501) (.756) (• 673) C269) -19- (208) (.300) (.046) ** The paper size of this paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1228980 A7 B7 V. Description of the invention ( 17) -227 .131 '087' 034 '032 • 139 • 111 CDH3 (.027) ** (288) (.401) (.750) (.760) (.185) (.320) ETS1 1 2 • 026 '013 -.052 .021' 148 '016 257 (.801) (.916) (.615) (.841) (• 157) (.881) (.020) ** -.403 • 111 -247 .099 • 051 '027 .104 ICAM2 (.000) ** (369) (.016) ** (347) (.630) (.798) (354) 255 .372 .049' 074 '174 202 • 165 Π15 3 (.013) ** (.000) ** (.636) (.484) (.095) * (.053) * (• 139) -.100 '013 .024 .047 • 133 .108. 106 Π5 receptor α3 Lymphopeptin β (• 334) 1 (• 914) (• 817) (.655) (203) (.305) (.342) • 074 -.012 -.045 .030 .035 • 051 .109 (Lynphotactin beta) (.485) (• 924) (.665) (• 774) (203) (.627) (.330) -238 -.050 -.091 .066 .084 .173 212 MUC2 2 (.020) ** (.083) * (• 381 ) (• 534) (• 425) (.100) (.007) ** • 020 -238 .064 -.104-• 185 • 045 293 PTGER2 (.846) (.050) ** (.537) ( 323) (.076) * (• 672) (.007) ** -.122 -.057 -.061 .046 .060 • 137 255 STAT4 (239) (.646) (.560) (.664) ( .569) (.192) (.021) ** -206 -.035 -.130 -.056 -.062 -.026 209 Aldehyde dehydrogenase 1 (.045) ** (.780) (• 593) (.553) (.809) (.059) * -.199 -.070 -239 -.073 .009 • 135 .059 CD30 (.053) * (• 572) (.020) ** (.488) (.933) (200) (.599)

•裝訂• Binding

绛 ____-20- 本紙張尺度適用中國國家標準(CNS) A4規格(210X29.7公釐） 1228980 訂绛 ____- 20- This paper size applies to China National Standard (CNS) A4 (210X29.7mm) 1228980 Order

A7 B7 五、發明説明 (is ) .002 214 .073 -.130 '133 266 .124 CEBPB (.986) (.079)* (•481) (217) (204) (.010)** (269) 233 •158 .043 .006 '082 .194 .045 GATA1 (.023)** (.987) (.682) (•955) (.432) (.069)* (.691) •128 -.001 .012 .042 '035 .079 .100 干擾素1 (218) (.993) (.908) (•693) (.738) (.452) (.370) '115 •018 '163 '012 -.089 -.001 226 IL15 4 (267) (.885) (.114) (.913) (.396) (.989) (.041)** •318 203 -.004 '077 -.112 •142 -.082 EL6 (.002)** (.097)* (.968) (.467) (283) (•176) (.463) -.121 •075 -.007 .057 •078 252 •112 MCP-3 0245) (.543) (.949) (•592) (.456) (.015)** (.316) -.108 -.147 -.035 '077 -•138 •034 215 MUC2 3 ¢295) (232) (.733) (.466) (•187) (.748) (.053)* 204 •330 .021 -.129 -.124 225 •026 RANEES (.047)** (.006)** (.840) (220) (238) (.031)** (.815) '124 -.094 '089 •121 •121 .003 •158 STAT4 2 (230) (.452) (.392) 0252) (246) (.979) (.156) ANVA^ 234 .193 .050 -.094 -.098 •158 .001 (.023)** (.114) (.628) (•374) (.348) (.132) (.991) '007 •170 •108 •016 '025 •187 .144 CD30 2 (.944) (.166) (298) (.883) (•814) (.074)* (.198) .333 -.102 .080 •Oil -.027 .198 •153 ofos (.001)** (.406) (.442) (•914) -21 - (•794) (.059)* (•170) 裝本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1228980 A7 B7 五、發明説明 (19 ) -222 '032 -.092 .033 .023 .192 266 GATA3 (.030)** (•795) (.376) (.755) (.824) (.067)* (.016)** -.062 •022 '144 '079 '119 '002 •128 IL10 (.549) (.860) (.164) (.456) (257) (.986) 〇251) .189 259 '016 -.058 -.123 227 -.001 IL18 (.066)* (.033)** (.881) (.581) C240) (.029)** C991) '139 -.095 -.140 •011 '016 •074 .122 IRF4一3 (•179) (.440) C177) (•918) (.880) (.486) (274) 金屬硫蛋白-.408 '059 -201 •053 •015 •054 219 —4 (.000)** (.631) (.051)* (.615) (.884) (.612) (.048)** -218 -228 -.092 -.033 .054 .162 203 MUC2一4 0〇34) (.062)* (.374) (•757) (.608) (•122) (.068)* •307 291 •026 -220 -218 .171 '049 SCYA17 (.002)** (.016)** (.804) (.035)** (.036)** (•104) (.661) '156 '113 .001 •028 .065 .006 .101 STAT4一3 (.131) (357) (.991) (.788) (.536) (.958) (.368) 註：** P<0.05; *P<0.1 用於建立氣喘指數之氣喘相關基因表現之參數列於表 2 ：表2 基因型參數 P值 R2 氣喘 3.93 0.706 評分 (0.000) -22- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1228980 A7 B7 五、發明説明（2Q ) ACHE -0.140 CD3 1 0.866 IL12受體β 2 -0.127 金屬硫蛋白 1.711 MUC2 -.1 08 SC ΥΑ4 3.260 STAT6 0.725 GBP2 4.478 IL4 -5.707 IRF4_2 -0.457 選擇素_L 1.560 腺甞酸環化酶1 -3.660 CCR5 1.788 CD38 0.034 IL13 2.778 IL4受體a -6.390 SLAM 0.5 13 TBXA2R_2 -4.276 CCR7 -1.519 IL15 -0.218 IL5受體α -0.893 ITGB7 -2.400 PDPK 2.762 _-23- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1228980 Α7 Β7 五、發明説明（21 ) STAT1 -2.458 LAMR1 2.920 CDH3 -0.470 IC ΑΜ2 0.066 醛脫氫酶1 -2.534 CD30 -0.146 GATA1 -2.006 IL6 -3.633 RANTES -4.335 ΑΝΧΑ3 2.87 1 C-FOS 1.567 GATA3 1.149 SCYA17 10.946 此外，FEV %之值及氣喘相關基因表現之參數列於表 D · 表3 迴歸模型基因型參數 Ρ值 R2 FEV% SCYA4 3.594 34.75 0.814 GBP2 6.037 (0.000) IL4 -9.400 IL 1 5-3 2.576 PTGER2 1.945 IL6 1.189 -24- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1228980 A7 --——______Β7 五、發明説明（22 ) RANTES 4.093 IL18 -8.355 __MUC2_4_0,191 _ 根據氣喘評分，使用表2之數據及皮耳森相關與多重線性迴歸處理而得之關係式：氣喘指數0.140(ACHE) + 0.866(CD3 1) 一〇.127(IL2 受體 β2)+1.711(金屬硫蛋白）一0.108(MUC2) + 3.260(SCYA4) + 0.725(STAT6) + 4.748(GBP2)-5.707(IL4) - 〇.457(IRF4__2) + 1.560(選擇素 _L) 一 3.660(腺茹酸環化酶 i)+ i.788(CCR5) + 0.034(CD38) + 2.778(IL13) — 6.390(IL4 受體 α) + 〇.5 13(SLAM) — 4.276(TBXA2R一2) — 1.519(CCR7) — 〇.218(IL15) -〇.893(IL5 受體〇〇 — 2.400(1丁087) + 2.762(?0?1〇 — 2·4 5 8(STAT 1 ) + 2.92 0(LAMRl) - 0.470(CDH3) + 0.066(ICAM2) - 2.534(酸脫氫酶 1) — 〇.i46(CD30) - 2.006(GATA 1 ) - 3.63 3 (IL6) - 4.3 5 5 (R ANTE S) + 2.871(ANXA3) + 1.567(C-FOS) + 1.149(GATA3) + 1 0.946(SCYA17) 根據F E V %，使用表3之數據而得之關係式：根據FEV°/。之氣喘指數=3.594(SCYA4) + 6.03 7(GBP2) - 9.400(IL4) + 2.5 7 6 (IL 1 5 - 3 ) + 1.945(PTGER2) + 1.189(IL6) + 4 . 〇 9 3 (R ANTE S)-8.355(IL18) + 0.191(MUC2^4) -25- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1228980 五、發明説明（23 魅 2 ·· 品。將經選擇與L:;:二實例1所得… n而有基因的表現料以定量及正規础謝ma lzed)，且使用該基因表現值以關係式計算各個 g乱喘指數，依氣喘評分所得之關係式計算之氣喘指數及依FEV%所得之關係式計算之氣喘指數，其變異量分別為 70·6%(Ρ<〇.05)& 81 4%(p<〇〇5)。 •裝雖2本說明書中已說明及描述本發明之具體例，但熟知本技蟄者可作各種修飾及改良。因此本發明具體例僅為說明性描述而非用以限制本發明之範圍。需了解本發明不限於所述特足類型，且不脫離本發明精神及範圍下之所有修正均在本發明申請專利範圍内。 -26- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）A7 B7 V. Description of the invention (is) .002 214 .073 -.130 '133 266 .124 CEBPB (.986) (.079) * (• 481) (217) (204) (.010) ** (269 ) 233 • 158 .043 .006 '082 .194 .045 GATA1 (.023) ** (.987) (.682) (• 955) (.432) (.069) * (.691) • 128-. 001 .012 .042 '035 .079 .100 Interferon 1 (218) (.993) (.908) (• 693) (.738) (.452) (.370)' 115 • 018 '163' 012- .089 -.001 226 IL15 4 (267) (.885) (.114) (.913) (.396) (.989) (.041) ** • 318 203 -.004 '077 -.112 • 142 -.082 EL6 (.002) ** (.097) * (.968) (.467) (283) (• 176) (.463) -.121 • 075 -.007 .057 • 078 252 • 112 MCP -3 0245) (.543) (.949) (• 592) (.456) (.015) ** (.316) -.108 -.147 -.035 '077-• 138 • 034 215 MUC2 3 ¢ 295) (232) (.733) (.466) (• 187) (.748) (.053) * 204 • 330 .021 -.129 -.124 225 • 026 RANEES (.047) ** (.006 ) ** (.840) (220) (238) (.031) ** (.815) '124 -.094' 089 • 121 • 121 .003 • 158 STAT4 2 (230) (.452) (.392 ) 0252) (246) (.979) (.156) ANVA ^ 234 .193 .050 -.094 -.098 • 158 .001 (.023) ** (.114) (.628) (• 374) (.348) (.132) (.991) '007 • 170 • 108 • 016' 025 • 187 .144 CD30 2 (.944) (.166) (298) (.883) (• 814) (.074) * (.198) .333 -.102 .080 • Oil -.027 .198 • 153 ofos (.001) ** (.406 ) (.442) (• 914) -21-(• 794) (.059) * (• 170) The size of this paper is applicable to China National Standard (CNS) A4 (210 x 297 mm) 1228980 A7 B7 V. Description of the invention (19) -222 '032 -.092 .033 .023 .192 266 GATA3 (.030) ** (• 795) (.376) (.755) (.824) (.067) * (.016 ) ** -.062 • 022 '144' 079 '119' 002 • 128 IL10 (.549) (.860) (.164) (.456) (257) (.986) 〇251) .189 259 '016 -.058 -.123 227 -.001 IL18 (.066) * (.033) ** (.881) (.581) C240) (.029) ** C991) '139 -.095 -.140 • 011 '016 • 074 .122 IRF4-1 (• 179) (.440) C177) (• 918) (.880) (.486) (274) Metallothionein-.408' 059 -201 • 053 • 015 • 054 219 —4 (.000) ** (.631) (.051) * (.615) (.884) (.612) (.048) ** -218 -228 -.092 -.033 .054 .162 203 MUC2-4 0〇34) (.062) * (.374) (• 757) (.608) ( 122) (.068) * • 307 291 • 026 -220 -218 .171 '049 SCYA17 (.002) ** (.016) ** (.804) (.035) ** (.036) ** ( • 104) (.661) '156' 113 .001 • 028 .065 .006 .101 STAT4 a 3 (.131) (357) (.991) (.788) (.536) (.958) (.368) ) Note: ** P <0.05; * P < 0.1 The parameters of asthma-related genes for establishing asthma index are listed in Table 2: Table 2 Genotype parameter P value R2 Asthma 3.93 0.706 Score (0.000) -22- This paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1228980 A7 B7 V. Description of invention (2Q) ACHE -0.140 CD3 1 0.866 IL12 receptor β 2 -0.127 Metallothionein 1.711 MUC2 -.1 08 SC ΥΑ4 3.260 STAT6 0.725 GBP2 4.478 IL4 -5.707 IRF4_2 -0.457 selectin_L 1.560 adenylate cyclase 1 -3.660 CCR5 1.788 CD38 0.034 IL13 2.778 IL4 receptor a -6.390 SLAM 0.5 13 TBXA2R_2 -4.276 CCR7 -1.519 IL15 -0.218 IL5 receptor α -0.893 ITGB7 -2.400 PDPK 2.762 _-23- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1228980 Α7 Β7 V. Description of the invention (21) STAT1 -2.458 LAMR1 2.920 CDH3 -0.470 IC ΑM2 0.066 Aldehyde dehydrogenase 1 -2.534 CD30 -0.146 GATA1 -2.006 IL6 -3.633 RANTES -4.335 ΑΝΑ3 2.87 1 C-FOS 1.567 GATA3 1.149 SCYA17 10.946 In addition, The values of FEV% and the parameters of asthma-related gene performance are listed in Table D. Table 3 Regression model genotype parameter P value R2 FEV% SCYA4 3.594 34.75 0.814 GBP2 6.037 (0.000) IL4 -9.400 IL 1 5-3 2.576 PTGER2 1.945 IL6 1.189 -24- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1228980 A7 ------______ B7 V. Description of invention (22) RANTES 4.093 IL18 -8.355 __MUC2_4_0,191 _ According to the asthma score, use the table The data of 2 and the relationship between Pearson correlation and multiple linear regression processing: asthma index 0.140 (ACHE) + 0.866 (CD3 1)-10.127 (IL2 receptor β2) + 1.711 (metallothionein)-0.108 (MUC2) + 3.260 (SCYA4) + 0.725 (STAT6) + 4.748 (GBP2) -5.707 (IL4)-〇.457 (IRF4__2) + 1.560 (selectin_L) -3.660 (adenosyl cyclase i) + i.788 (CCR5) + 0.034 (CD38 ) + 2.778 (IL13) — 6.390 (IL4 receptor α) + 0.5 13 (SLAM) — 4.276 (TBXA2R-2) — 1.519 (CCR7) — 0.218 (IL15) — 0.983 (IL5 receptor) 〇— 2.400 (1 087) + 2.762 (? 0? 1 〇— 2. 4 5 8 (STAT 1) + 2.92 0 (LAMRl)-0.470 (CDH3) + 0.066 (ICAM2)-2.534 (acid dehydrogenase 1 ) — 〇.i46 (CD30)-2.006 (GATA 1)-3.63 3 (IL6)-4.3 5 5 (R ANTE S) + 2.871 (ANXA3) + 1.567 (C-FOS) + 1.149 (GATA3) + 1 0.946 ( SCYA17) According to FEV%, the relationship is obtained using the data in Table 3: According to FEV ° /. Asthma Index = 3.594 (SCYA4) + 6.03 7 (GBP2)-9.400 (IL4) + 2.5 7 6 (IL 1 5-3) + 1.945 (PTGER2) + 1.189 (IL6) + 4. 〇9 3 (R ANTE S ) -8.355 (IL18) + 0.191 (MUC2 ^ 4) -25- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1228980 V. Description of the invention (23 Charm 2 ... Select the relationship between L:;: 2 obtained in Example 1 ... n and gene expression data (quantitative and regular basis (ma lzed), and use the gene expression value to calculate each g disorder asthma index in a relational expression, based on the asthma score. The asthma index calculated by the formula and the asthma index calculated by the relationship obtained by FEV%, the variation amounts were 70.6% (P < 0.05) & 81 4% (p < 0.05). • Equipment Although specific examples of the present invention have been described and described in this specification, those skilled in the art can make various modifications and improvements. Therefore, the specific examples of the present invention are merely illustrative descriptions, not intended to limit the scope of the present invention. It should be understood that the present invention is not limited to the special foot type, and all modifications that do not depart from the spirit and scope of the present invention are within the scope of the present invention. -26- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims

1228980 第091117315號專利申請案 — 中文申請專利範圍替換本(93年10月)益申請專利範園 1· 一種建立診斷及/或_ —個體之複合性基因疾病指數之方法，其包括下列步驟： ⑷在該個體中測量經選擇與該複合性基因疾病有關之一個以上之基因之表現值；㈨使用-關係式計算該表現值而得一指數，該指數代表該個體罹患該複合性基因疾病之機率及/或嚴重性；其中步驟（b)之關係式係由包含下列步驟之方法而得：裝 ⑴評估-群患有該複合性基因疾病之病患之病況評分（condition scores)； ⑴）測量該等病患就經選擇與該複合性基因疾病有關之基因之表現值；及 (出）將步驟⑴及（ii)所得病患之病況評分與基因表現值進行統計學分析及迴歸處理而得該關係式。 2. 如申請專利範圍第丨項之方法，其中步驟（a)中之基因表現值可藉晶片或聚合酶鏈反應測量。、線 3. 如申請專利範圍第2項之方法，其中欲測量其因係得自個體血液樣品。因 4·如申請專利範圍第2項之方法，其中步驟⑴）中之基表現值係藉晶片或聚合酶鏈反應測量。土況關 5. 如申請專利範圍第之方法，其中步帮（出）中之病評分及表現值之統計學分析及迴歸處理係皮耳森= (Pearson correiati〇n)及多重線性迴歸分析。目 6. 如申請專利範圍第丨項之方法，其中步驟⑴中之病況評 78247-931026.doc ^ a 本紙張尺度適用中_家鱗(CNS) Μ規格⑵㈣97公酱)1228980 Patent Application No. 091117315-Replacement of the Chinese patent application scope (October 1993) Yi Application Patent Fanyuan 1. A method for establishing a diagnostic and / or _ composite genetic disease index for individuals, including the following steps:测量 Measure the performance value of more than one gene selected in the individual related to the composite genetic disease; 计算 Use the -relational formula to calculate the performance value to obtain an index, which represents the individual suffering from the composite genetic disease. Probability and / or severity; where the relationship of step (b) is obtained by a method comprising the following steps: Decoration assessment-condition scores of a group of patients with the complex genetic disease; ⑴) Measure the performance values of these patients by selecting genes related to the complex genetic disease; and (out) statistically analyze and regression process the condition scores and gene performance values of the patients obtained in steps ii and (ii) Get the relationship. 2. The method according to item 丨 of the patent application, wherein the gene expression value in step (a) can be measured by wafer or polymerase chain reaction. 3. The method as described in item 2 of the patent application, in which the cause to be measured is obtained from an individual blood sample. Because 4. The method of item 2 in the scope of patent application, wherein the performance value of step ii) is measured by wafer or polymerase chain reaction. Soil Condition Close 5. As the method of applying for the scope of patent application, the statistical analysis and regression processing of disease scores and performance values in the step (out) are Pearson Correiatión and multiple linear regression analysis. Item 6. For the method of applying for the item No. 丨 in the scope of patent application, in which the condition in step 247 is evaluated 78247-931026.doc ^ a This paper size is applicable _ home scale (CNS Μ size ⑵㈣ 97 male sauce)

$係藉病歷史、身體檢查、試驗檢測及/或放射線診斷而得。一種建立診斷及/或預判一個體之氣喘指數之方法，其包括下列步驟： (a) 在該個體中測量經選擇與氣喘有關之一個以上之基因之表現值； (b) 使用一關係式計算該表現值而得一氣喘指數，該氧喘指數代表該個體罹患氣喘之機率及/或嚴重性；其中步驟（b)之關係式係由包含下列步驟之方法而得： (0 坪估一群患有氣喘之病患之病況評分； (11)測量該等病患就經選擇與氣喘有關之基因之表現值；及 (出）將步驟⑴及（ii)所得病患之病況評分及基因表現值進行統計學分析及迴歸處理而得該關係式。如申清專利範圍第7項之方法，其中欲測量其表現之其因係得自個體血液樣品。基 9 如申請專利範圍第7項之方法，其中步驟（a)中之基因表現值係藉晶片或聚合酶鏈反應測定。、 10·如申請專利範圍第7項之方法’其中步驟⑴)中表現值係藉晶片或聚合酶鏈反應測量。土、 Π·如申請專利範圍第7項之方法，其中步驟（ιΗ)中、、、、評分及表現值之統計學分析及迴歸處理爻两况及多重線性迴歸分析。 “皮耳森相關 78247-931026.doc -2 - 1228980 A8 B8 ----- S8 ^ ------—_____D8 穴、申請專利一~" 12·如申請專利範圍第7項之方法，其中經選擇與氣喘有關足基因包括編碼細胞素之基因、編碼受體之基因、編碼轉錄因子之基因、編碼發訊分子之基因、編碼化學增活素之基因、編碼黏著分子之基因、或其組合。 •如申明專利範圍第7項之方法，其中病況評分係選自由以下組成之群組··氣喘評分、醫藥評分、類固醇評分、1秒内用力呼氣量（FEVl)、高峰呼氣流量 (PEFR)、用力肺活量（FVC)、IgE量、對抗原特異之 UE、嗜伊紅血球及嗜伊紅性血球陽離子蛋白質量及其組合。 14·如申請專利範圍第7項之方法，其中步驟〇)中之病況評分係藉病歷史、身體檢查、試驗檢測及/或放射線診斷而得。 -3 - 78247-931026.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)$ Is derived from medical history, physical examination, laboratory tests and / or radiological diagnosis. A method for establishing a diagnosis and / or prediction of an individual's asthma index, comprising the following steps: (a) measuring the performance value of more than one gene selected for asthma in the individual; (b) using a relationship Calculate the performance value to obtain an asthma index, which represents the probability and / or severity of asthma in the individual; where the relationship of step (b) is obtained by a method including the following steps: (0) Patients with asthma scores; (11) Measure the performance values of these patients for genes selected for asthma; and (out) the condition scores and gene performance of the patients obtained in steps ii and (ii) The relationship is obtained by statistical analysis and regression processing. For example, the method of claim 7 of the patent scope, in which the reason for measuring its performance is obtained from an individual blood sample. Method, wherein the gene expression value in step (a) is determined by using a wafer or a polymerase chain reaction. 10. The method according to item 7 of the patent application 'wherein step ii) is performed by using a wafer or a polymer. Ligase chain reaction measurement. The method of item 7 in the scope of patent application, in which the statistical analysis and regression processing of the scores, performance values, and regression in the step (ιΗ) 爻 two-state and multiple linear regression analysis. "Pearson-related 78247-931026.doc -2-1228980 A8 B8 ----- S8 ^ ---------- __D8 hole, apply for a patent ~ &12; such as the method of applying for the scope of patent No. 7 Among them, the selected asthma-related foot genes include genes encoding cytokines, genes encoding receptors, genes encoding transcription factors, genes encoding signaling molecules, genes encoding chemoactivin, genes encoding adhesion molecules, or The combination of the methods as stated in item 7 of the patent scope, wherein the condition score is selected from the group consisting of: asthma score, medical score, steroid score, forced expiratory volume within 1 second (FEVl), peak breath Flow rate (PEFR), forced vital capacity (FVC), amount of IgE, antigen-specific UE, eosinophil and eosinophil cationic protein mass, and a combination thereof. 14. The method as claimed in item 7 of the patent application, wherein the steps 〇) The condition score is based on the history of the disease, physical examination, test and / or radiation diagnosis. -3-78247-931026.doc This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm)