尋找與肌萎縮性側索硬化症相關的過去病史：全人口病例對照研究

Abstract

研究重要性： 在過去二十多年，許多研究發現與肌萎縮性側索硬化症（amyotrophic lateral sclerosis, ALS）有相關之疾病危險因子，但是卻少有研究將這些疾病在ALS發病之前的罹患時間納入討論。 研究目標： 探討ALS診斷日之前的疾病罹患情況來揭示與ALS有關之過去病史。 研究設計： 本研究為全人口病例對照研究。研究起始點為第一次ALS診斷日。 研究資料： 本研究使用全民健保資料庫（National Health Insurance Database, NHID）以及重大傷病資料庫（Serious Disabling Disease Database, SDD）。 研究對象： 從2007年1月1日至2013年12月31日止，共有705位15歲以上之ALS新發病例。將這些ALS病例以性別、年齡、居住地、以及投保薪資進行配對，配對比為1:20，得到14,100位對照組。 研究暴露： 篩選出ALS診斷日1 年前、3年前、5年前、7年前，以及9年前之過去病史，藉以評估該疾病發生是否為ALS的獨立變項。我們排除在首次診斷出ALS之前的1、1~2、1~4、1~6、1~8年間的疾病紀錄；疾病定義採用國際疾病分類碼第九版（International Classification of Diseases, 9th revision, ICD-9）的前三位數。 主要結果測量： 利用台灣衛生福利部之重大傷病資料庫（SDD）中的疾病紀錄，ALS 的ICD-9病例編碼為335.20。 統計分析： 以卡方檢定或T檢定檢查ALS新發病例與對照組間的人口學特徵之差異。首先使用單變數條件邏輯式廻歸模型篩選出過去病史，再藉由偽發現率（false discovery rate, FDR）調整p值，避免膨脹偽陽性。以偽發現率（FDR）調整後的p值<0.10作為相關疾病的初步篩選依據。除了經由單變數分析篩選疾病外，另外也進行多變數分析來評估先前疾病與ALS罹患風險之間的關聯。之後使用路徑分析（Path Analysis）來分析ALS病例及過去病史的關係網絡並討論之疾病間的影響力。 結果： 因配對研究設計的緣故，ALS患者平均年齡56.65 ± 11.38歲（平均值±標準差）與對照組相同；在705例ALS患者中，男性400例，女性305例（男女比為1.3：1）；50例患者住在鄉村，近一半的ALS病例為接受社會福利補助或家庭的依附投保成員。 本研究多變數分析結果共篩選出28項過去病史與ALS有顯著相關，其中正相關疾病有17項，負相關疾病有11項。一般檢查（ICD-9:V70，OR=1.3，九年以前），耳朵疾病（ICD-9:388，OR=1.6，九年以前），膝內障礙（ICD-9:717，OR=1.9，五年以前），椎間盤疾患（ICD-9:722，OR=1.4，五年以前），頭臉頸部狀挫傷（ICD-9:920，OR=1.5，五年以前），神經根及神經叢疾患（ICD-9:353，OR=1.5，三年以前），營養、新陳代謝和發育的症狀（ICD-9:783，OR=2.1，三年以前），病毒性疫苗接種（ICD-9:V04，OR=1.4，一年以前），其他錐體外疾病及不正常動作疾病（ICD-9:333，OR=1.9，一年以前），上肢神經炎（ICD-9:354，OR=1.3，一年以前），下肢單一神經炎（ICD-9:355，OR=1.5，一年以前），末梢神經病變（ICD-9:356，OR=1.7，一年以前），發炎性及中毒性神經病變（ICD-9:357，OR=1.7，一年以前），腦動脈阻塞（ICD-9:434，OR=1.6，一年以前），氣喘（ICD-9:493，OR=1.3，一年以前），蜂窩性組織炎（ICD-9:682，OR=1.3，一年以前），脊椎關節病（ICD-9:721，OR=1.2，一年以前），肌肉、韌帶及筋膜疾患（ICD-9:728，OR=1.4，一年以前）與ALS呈顯著正相關。 另外，與ALS呈顯著負相關的過去疾病有糖尿病（ICD-9:250，OR=0.7，五年以前），皮膚和皮下組織障礙（ICD-9:709，OR=0.7，五年以前），慢性缺血性心臟病（ICD-9:414，OR=0.8，三年以前），牙齒硬組織疾病（ICD-9:521，OR=0.8，三年以前），十二指腸潰瘍（ICD-9:532，OR=0.7，三年以前），癰及癤（ICD-9:680，OR=0.7，三年以前），下肢挫傷（ICD-9:924，OR=0.8，三年以前），追蹤檢查（ICD-9:V67，OR=0.7，一年以前），中耳炎（ICD-9:382，OR=0.6，一年以前），胃功能障礙（ICD-9:536，OR=0.8，一年以前），類風溼性關節炎（ICD-9:714，OR=0.7，一年以前）。 路徑分析顯示與ALS有負相關的11個疾病可歸納為糖尿病及其相關併發症；與ALS有正相關的17個疾病可歸納為新陳代謝異常、神經發炎、頭部外傷、運動傷害、感染等。 結論： 通過這些結果，我們可以假設高代謝綜合症疾病是ALS的可能成因，其保護因子為代謝綜合症疾病。Importance: Although many studies over the last 20 years have discovered diseases that may increase or decrease the risk of amyotrophic lateral sclerosis (ALS), inconsistent and ambiguous results muddle the direction of these associations. Objective: We investigated prior diseases associated with ALS using a total population-based medical claims database. Design: This was a total population-based case–control study. The index date was set as the date of diagnosis of ALS. Setting: This study was conducted using the National Health Insurance Research Database (NHIRD) and Serious Disabling Diseases (SDD) database in Taiwan. Participants: We included 705 new ALS cases aged more than 15 years from January 1, 2007, to December 31, 2013, and 14,100 sex-, age-, residence-, and insurance premium-matched controls. Exposure: Prior diseases were stratified as being diagnosed 1, 3, 5, 7, and 9 years prior to the ALS diagnosis date. Diseases were identified using the first 3 digits of International Classification of Diseases, ninth revision (ICD-9). Main Outcome Measure: ALS was classified according to the ICD-9 (335.20) by SDD database from Department of Health and Welfare, Taiwan. Statistics analysis: Chi-squared or t-test was used to examine differences in demographic characteristics between new patients with ALS and controls. Prior diseases were first screened using conditional logistic regression model. The false discovery rate (FDR)-adjusted P value was then reported to avoid inflating false positives. A disease with FDR-adjusted P<0.10 was considered as a significantly associated disease. After the significant prior diseases were found using univariate analysis, multivariate analysis was performed using stepwise selection to evaluate the association between these diseases and the risk of ALS. We also used the path analysis to analyze the pathway between prior diseases and ALS. The effects of prior diseases on ALS were also estimated. Result: The mean (± standard deviation) age of patients with ALS was 56.65 ± 11.38 years. Of 705 patients with ALS, 400 were males and 305 were females (1.3:1). Only 50 ALS cases lived in rural areas. Nearly half of the ALS cases were under social welfare or supported by family members. In this study, 28 prior diseases were associated with ALS, including 17 positive and 11 negative associations. Diseases positively associated with ALS were the following: general medical examination (ICD-9: V70, OR=1.3, before 9 years), internal derangement of knee (ICD-9: 717, OR=1.9, before 5 years), intervertebral disc disorders (ICD-9: 722, OR=1.4, before 5 years), contusion of the face, scalp, and neck (ICD-9: 920, OR=1.5, before 5 years), nerve root and plexus disorders (ICD-9: 353, OR=1.5, before 3 years), symptoms concerning nutrition, metabolism, and development (ICD-9: 783, OR=2.1, before 3 years), need for prophylactic vaccination and inoculation against certain diseases (ICD-9: V04, OR=1.4, before 1 year), other extrapyramidal disease and abnormal movement disorders (ICD-9:333, OR=1.9, before 1 years), mononeuritis of the upper limb and mononeuritis multiplex (ICD-9: 354, OR=1.3, before 1 year), mononeuritis of the lower limb (ICD-9: 355, OR=1.5, before 1 year), hereditary and idiopathic peripheral neuropathy(ICD-9: 356, OR=1.7, before 1 year), inflammatory and toxic neuropathy (ICD-9: 357, OR=1.7, before 1 year), occlusion of cerebral arteries (ICD-9: 434, OR=1.6, before 1 year), asthma (ICD-9: 493, OR=1.3 before 1 year), other cellulitis and abscess (ICD-9: 682, OR=1.3, before 1 year), spondylosis and allied disorders (ICD-9:721, OR=1.2, before 1 year), and disorders of the muscle, ligament, and fascia (ICD-9:728, OR=1.4, before 1 year. Diseases negatively associated with ALS were as follows: diabetes mellitus (ICD-9:250, OR=0.7 , before 5 years), other disorders of the skin and subcutaneous tissue (ICD-9:709, OR=0.7 , before 5 years), other forms of chronic ischemic heart disease (ICD-9:414, OR=0.8 , before 3 years), diseases of the hard tissues of the teeth (ICD-9:521, OR=0.8 , before 3 years), duodenal ulcer (ICD-9:532, OR=0.7 , before 3 years), carbuncle and furuncle (ICD-9:680, OR=0.7 , before 3 years), contusion of the lower limb (ICD-9:924, OR=0.8 , before 3 years), follow-up examination (ICD-9:V67, OR=0.7 , before 1 year), otitis media (ICD-9:382, OR=0.6 , before 1 year), disorders of function of the stomach (ICD-9:536, OR=0.8 , before 1 year), rheumatoid arthritis and other inflammatory polyarthropathies (ICD-9:714, OR=0.7 , before 1 year). Moreover, path analysis showed that the 11 negative association diseases can be considered as diabetes mellitus and its comorbidities. The 17 positive association diseases can be considered as metabolic syndrome, neuroinflammation, head trauma, sports injuries, infections, and their comorbidities. Conclusion: Our results supported the hypothesis that prior diseases for ALS were hypermetabolic syndrome diseases. Moreover, the hypometabolic syndrome diseases may have a beneficial effect on ALS incidence.