摘要:目的本文旨在肌肉脂肪浸潤的基礎(chǔ)上,利用分層分析的方法將肌肉內(nèi)部按照不同的密度范圍劃分成不同的亞分區(qū),進一步研究肌肉密度改變對原位肝移植術(shù)(OLT)后并發(fā)癥(Clavien-Dindo≥Ⅲ)的影響。方法回顧性分析2013年5月—2020年9月于吉林大學第一醫(yī)院行OLT的145例患者,以患者腰3椎體水平最大層面的CT平掃圖像作為原始數(shù)據(jù),利用Neusoft Fatanalysis軟件對圖像進行相關(guān)肌肉參數(shù)的測量。符合正態(tài)分布的計量資料組間比較采用成組t檢驗;不符合正態(tài)分布的組間比較采用Mann-Whitney U秩和檢驗。計數(shù)資料組間比較采用χ2或Fisher檢驗。利用RIAS軟件進行臨床特征提取及分析建模,分別建立邏輯回歸(LR)、支持向量機(SVM)、隨機森林(RFC)3種機器學習模型,并繪制不同模型的受試者操作特征曲線(ROC曲線)、校正曲線、決策分析曲線,計算ROC曲線下面積(AUC)、靈敏度、特異度、精確率、F1分數(shù)、準確率。結(jié)果采用肌肉分層分析前的7種臨床特征建立LR-C、SVM-C、RFC-C 3種機器學習模型,其中RFC-C模型測試集的AUC值為0.803、靈敏度0.588,特異度0.778。采用肌肉分層分析后的16種臨床特征建立的LR-CS、SVM-CS、RFC-CS模型中,LR-CS及SVM-CS模型測試集的AUC值較高,均為0.852,靈敏度分別為0.765、0.706,特異度分別為0.889、0.926,通過對比肌肉分層分析前后各模型測試集的AUC、靈敏度、特異度、精確率、F1分數(shù)、準確率后發(fā)現(xiàn),肌肉分層分析后預(yù)測模型的參數(shù)均有所提升。通過對比各預(yù)測模型的決策分析曲線和校正曲線,發(fā)現(xiàn)LR-CS及SVM-CS模型對于預(yù)測OLT患者術(shù)后并發(fā)癥(Clavien-Dindo≥Ⅲ)具有良好效能。結(jié)論在肌肉脂肪浸潤的基礎(chǔ)上,利用分層分析的方法將肌肉內(nèi)部按照不同的密度劃分成不同子區(qū),對于OLT患者術(shù)后并發(fā)癥有一定預(yù)測價值。
關(guān)鍵詞:肌肉脂肪浸潤;肝移植;手術(shù)后并發(fā)癥
基金項目:吉林省科技發(fā)展計劃基金(20220505017ZP)
Value of internal stratification analysis of abdominal wall muscles in predicting complications after orthotopic liver transplantation
SHI Xina,LIANG Chongxiaob,ZHANG Beia,WANG Jipinga
a.Department of Radiology,b.Department of Cardiac Ultrasound,The First Hospital of Jilin University,Changchun 130012,China
Corresponding author:WANG Jiping,jiping@jlu.edu.cn(ORCID:0000-0003-1991-4104)
Abstract:Objective To divide the muscle into different subzones according to different density ranges using the stratified analysis on the basis of myosteatosis,and to investigate the effect of muscle density changes on complications(Clavien-Dindo grade≥Ⅲ)after orthotopic liver transplantation(OLT).Methods A retrospective analysis was performed for the medical records of 145 patients who underwent OLT in The First Hospital of Jilin University from May 2013 to September 2020,and with the plain CT scan images of the largest level of lumbar 3 vertebrae of each patient as the original data,Neusoft Fatanalysis software was used to measure related muscle parameters.The independent-samples t test was used for comparison of normally distributed continuous data between two groups,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups.The chi-square test or Fisher test was for comparison of categorical data between two groups.RIAS software was used to extract clinical features and performanalysis and modeling,and three machine learning models of logistic regression(LR),support vector machine(SVM),and random forest(RFC)were constructed.The receiver operating characteristic(ROC)curve,the calibration curve,and the decision curve were plotted for each model to calculate the area under the ROC curve(AUC),sensitivity,specificity,precision,F(xiàn)1 score,and accuracy.Results The three machine learning models of LR-C,SVM-C,and RFC-C were established based on the 7 clinical features before muscle stratification analysis,among which the RFC-C model had an AUC of 0.803,asensitivity of 0.588,and a specificity of 0.778 in the test set.Among the models of LR-CS,SVM-CS,and RFC-CS established based on the 16 clinical features after muscle stratification analysis,the LR-CS and SVM-CS models had an AUC of 0.852 in the test set,with a sensitivity of 0.765 and 0.706,respectively,and a specificity of 0.889 and 0.926,respectively.Comparison of the AUC,sensitivity,specificity,precision,F(xiàn)1 score,and accuracy of each model in the test set before and after muscle stratification analysis showed that there were improvements in the parameters of the predictive model after muscle stratification analysis.Comparison of the decision curves and calibration curves of each predictive model showed that the LR-CS and SVM-CS models had good efficacy in predicting postoperative complications(Clavien-Dindo grade≥Ⅲ)in OLT patients.Conclusion On the basis of myosteatosis,the division of the muscle into different subzones according"to different densities using the stratified analysis has a certain value in predicting postoperative complications in patients with OLT.
Key words:Myosteatosis;Liver Transplantation;Postoperative Complications
Research funding:Science and Technology Development Plan Fund of Jilin Province(20220505017ZP)
肌肉脂肪浸潤是指骨骼肌內(nèi)出現(xiàn)了異常的脂肪沉積,這是一種異位的脂肪儲存形式,隨著年齡的增長而逐漸增加,被認為與肌肉質(zhì)量、力量和活動能力下降等密切相關(guān),并且可擾亂新陳代謝[1]。目前對肌肉脂肪浸潤的發(fā)生機制研究甚少,但也有學者提出了一些理論及觀點,包括瘦素信號傳導(dǎo)缺陷[2],骨骼肌前體干細胞[3]或成纖維脂肪前體細胞[4]相關(guān)信號傳導(dǎo)機制破壞以及線粒體功能障礙等[5]。肝移植是終末期肝病有效的治療手段[6]。肝移植患者門靜脈壓力的調(diào)節(jié)、混合供體手術(shù)以及圍手術(shù)期患者肌肉質(zhì)量的改變,都會對術(shù)后短期預(yù)后產(chǎn)生影響[7]。因此,在肝移植過程中,供受體的手術(shù)風險評估尤為重要。在此之前已經(jīng)開發(fā)了多種風險評估模型,對肝移植患者術(shù)后預(yù)后評估具有一定的價值[8-12]。但在這些風險評估模型中,并沒有將身體成分改變納入評估標準。Czigany等[13]首次將肌肉脂肪浸潤作為評估指標與Dutkowski等[8]提出的BAR評分(Balance-of-Risk-Score)相結(jié)合,建立了全新的肝移植術(shù)后評估模型,其研究結(jié)果表明肌肉脂肪浸潤是預(yù)測同種異體原位肝移植術(shù)(orthotopic liver transplantation,OLT)患者圍手術(shù)期預(yù)后的重要參數(shù)。越來越多的證據(jù)表明肌肉脂肪浸潤在肝移植預(yù)后評估中起到重要作用[14-16]。目前,關(guān)于肌肉脂肪浸潤的評估可以通過侵入性的肌肉活檢進行量化,也可以通過使用非侵入性的成像設(shè)備進行量化,例如CT、定量CT(QCT)、磁共振成像(MRI)、定量超聲、磁共振波譜(MRS)等[1]。通過總結(jié)和歸納后發(fā)現(xiàn),目前診斷肌肉脂肪浸潤的影像學方法大多采用腹部CT平掃[17-18]。因此,本研究通過腹部CT平掃對肌肉內(nèi)部進行分層分析,進一步探索肌肉內(nèi)部密度改變,對肝移植術(shù)后并發(fā)癥的預(yù)測能力。由于肝移植術(shù)后并發(fā)癥種類較多且復(fù)雜,本研究采用國際通用的外科并發(fā)癥分級系統(tǒng)(Clavien-Dindo)對肝移植患者術(shù)后并發(fā)癥進行嚴重程度分級[19]。
1資料與方法
1.1研究對象納入2013年5月—2020年9月于本院行OLT的患者145例。納入標準:(1)患者年齡≥18歲;(2)患者術(shù)前1個月內(nèi)接受過腹部CT平掃檢查。排除標準:(1)腹部CT平掃圖像質(zhì)量差、偽影重,導(dǎo)致無法對腰3椎體水平肌肉進行相關(guān)指標的測量;(2)患者術(shù)后半年內(nèi)病歷信息不完整,未能按照規(guī)定時間隨訪。本研究所有合并肝細胞癌的患者均符合肝移植杭州標準[20]。
1.2研究方法
1.2.1臨床數(shù)據(jù)收集通過臨床病歷系統(tǒng)收集患者的人口學信息、入院時實驗室檢查以及既往病史,包括性別、年齡、身高、體質(zhì)量、身體質(zhì)量指數(shù)(BMI)、MELD評分、Child-Pugh評分、AST、ALT、總膽紅素、直接膽紅素、白蛋白、白細胞、PLT、PT、國際標準化比值(INR)、血Na+、肌酐、既往腹部手術(shù)史、是否合并糖尿病、肝細胞癌射頻消融治療情況、肝細胞癌動脈栓塞治療情況、是否存在難以控制的靜脈曲張出血、是否存在肝性腦病、是否存在移植術(shù)前感染等。
1.2.2 CT掃描參數(shù)及圖像獲取腹部CT平掃圖像來自于兩臺CT設(shè)備。第1臺CT:西門子雙源CT(Somatam Definition)。掃描參數(shù):層厚為5.0 mm,螺距為0.8 mm,旋轉(zhuǎn)時間為0.5 s,管電壓為120 kV,管電流為300 mA。第2臺CT:飛利浦Brilliance iCT。掃描參數(shù):層厚為5.0 mm,螺距為0.9 mm,旋轉(zhuǎn)時間為0.5 s,管電壓為120 kV,管電流為282 mA。通過放射科東軟工作站導(dǎo)出所有患者L3椎體水平最大層面CT平掃圖像(層厚5 mm)的DICOM數(shù)據(jù)作為原始圖像數(shù)據(jù),導(dǎo)入Neusoft Fatanalysis軟件(AVW 2.0.36.1237 2020/6/10)進行相關(guān)處理。
1.2.3 CT圖像處理及分層分析利用Neusoft Fatanalysis軟件按照閾值?30~150 HU半自動識別L3椎體水平最大層面全腹壁肌肉,再按照閾值為?190~?50 HU半自動識別皮下脂肪、腹腔脂肪,繼而得到皮下脂肪面積(SFA)、腹腔脂肪面積(VFA)、脂肪總面積(TFA)、VFA/TFA、腰圍、脂肪的平均CT值、肌肉指數(shù)(SMI)、全腹壁肌肉的平均CT值(SMRA)(圖1)。進一步通過軟件按照不同的密度范圍將肌肉內(nèi)部劃分成3種不同的亞分區(qū),并用不同的偽彩表示(圖2),分別定義為正常肌肉(NAMA)(30~150 HU,紅色)、輕度脂肪浸潤肌肉(LAMA)(0~30 HU,綠色)、嚴重脂肪浸潤肌肉(HAMA)(lt;0 HU,藍色),通過軟件自動計算NAMA、LAMA、HAMA 3種不同亞分區(qū)的面積、所占全腹壁肌肉總面積的百分比以及不同亞分區(qū)的SMRA。肌肉脂肪浸潤評估依據(jù)Martin等[21]建議的診斷截斷值得出,當BMIlt;25 kg/m2時,SMRAlt;41 HU;當BMI≥25 kg/m2時,SMRAlt;33 HU診斷為肌肉脂肪浸潤。
1.2.4臨床特征的篩選及模型的建立首先利用RIAS[22-23](www.riascloud.com)軟件將145例患者按照7∶3的比例隨機分成訓(xùn)練集(n=101)和測試集(n=44),然后將訓(xùn)練集中的患者按照是否出現(xiàn)并發(fā)癥(Clavien-Dindo≥Ⅲ)分成并發(fā)癥組和非并發(fā)癥組,比較兩組患者各項臨床特征的差異,將Plt;0.05的特征指標用于臨床預(yù)測模型的建立。本研究在建立機器學習模型的過程中對訓(xùn)練集采用了5折交叉驗證的方法,目的在于客觀綜合評估篩選出的臨床特征對研究問題的預(yù)測能力。首先將訓(xùn)練集平均分成5份,隨機選取其中1份作為驗證集,其余4份作為內(nèi)部訓(xùn)練集進行模型建立,該過程重復(fù)5次;然后利用整個訓(xùn)練集建立模型,利用測試集進行獨立驗證。本研究利用肌肉分層分析前后篩選出的臨床特征分別建立邏輯回歸(LR)、支持向量機(SVM)、隨機森林(RFC)3種機器學習模型。
1.3統(tǒng)計學方法應(yīng)用SPSS 25.0、RAIS、Medcalc 20.0.3軟件進行統(tǒng)計學分析。符合正態(tài)分布的計量資料采用±s表示,2組間比較采用成組t檢驗;不符合正態(tài)分布的計量資料用M(P25~P75)表示,2組間比較采用Mann-Whitney U秩和檢驗。計數(shù)資料2組間比較采用χ2檢驗或Fisher檢驗。利用RIAS軟件構(gòu)建LR、SVM、RFC機器學習模型,并繪制模型的受試者操作特征曲線(ROC曲線)、校正曲線、決策分析曲線,計算AUC值、靈敏度、特異度、精確率、F1分數(shù)、準確率,利用上述指標綜合評估各模型的診斷價值。利用Medcalc 20.0.3對各模型的ROC曲線進行Delong檢驗。Plt;0.05為差異有統(tǒng)計學意義。
2結(jié)果
2.1基本資料及臨床特征篩選共納入145例OLT患者,平均年齡(50.58±9.82)歲,其中乙型肝炎肝硬化88例(34例合并肝細胞癌、1例合并膽管細胞癌、1例合并肝性脊髓?。?,丙型肝炎肝硬化8例(2例合并肝細胞癌),酒精性肝硬化15例(1例合并肝細胞癌),乙型肝炎合并丙型肝炎肝硬化1例,原發(fā)性膽汁性肝硬化12例,不明原因肝硬化3例,原發(fā)性硬化性膽管炎2例,膽汁淤積性肝硬化2例,藥物性肝硬化4例,自身免疫性肝炎3例,單純肝細胞癌1例,肝門部膽管細胞癌1例,多囊肝1例,肝血吸蟲病1例,肝豆狀核變性1例,肝臟未分化胚胎肉瘤1例,特發(fā)性門靜脈高壓1例。
6個月內(nèi)出現(xiàn)并發(fā)癥(Clavien-Dindo≥Ⅲ)的患者共49例,訓(xùn)練集中有并發(fā)癥32例,測試集中有并發(fā)癥17例(表1)。CT圖像分析在觀察者間及觀察者內(nèi)顯示出了良好的重復(fù)性好,組內(nèi)相關(guān)系數(shù)(ICC)均gt;0.75。最終通過對訓(xùn)練集并發(fā)癥組與非并發(fā)癥組患者各項臨床指標的差異性比較,在肌肉分層分析前共篩選出了7個臨床特征包括:MELD評分、Child-Pugh評分、AST、白蛋白、糖尿病、肌肉脂肪浸潤、SMRA。肌肉分層分析后,通過組間差異性比較,又新篩選出了9個臨床特征,包括各亞區(qū)的SMI、所占全腹壁肌肉面積的百分比、SMRA,分別為NAMA-SMI、NAMA百分比、NAMA-SMRA、LAMA-SMI、LAMA百分比、LAMA-SMRA、HAMA-SMI、HAMA百分比、HAMA-SMRA。上述指標在訓(xùn)練集與測試集間均無統(tǒng)計學差異(P值均gt;0.05)(表2)。
2.2臨床預(yù)測模型的建立首先利用分層分析前篩選出的7個臨床特征建立LR-C、SVM-C、RFC-C模型,其中RFC-C模型(測試集)的AUC值較高(圖3),AUC值為0.803、靈敏度為0.588、特異度為0.778。其次,利用肌肉分層分析后共篩選出的16個臨床特征建立LR-CS、SVM-CS、RFC-CS模型,其中LR-CS及SVM-CS模型的AUC值相對較高(圖4、5),AUC值均為0.852,靈敏度分別為0.765、0.706,特異度分別為0.889、0.926,結(jié)果顯示肌肉分層分析后建立的臨床模型的ROC曲線各項參數(shù)相比肌肉分層分析前均有所提升,并且Delong檢驗顯示LR-CS與LR-C模型的AUC值存在明顯統(tǒng)計學差異(P=0.005)(表3)。繪制肌肉分層分析前后各模型的決策分析曲線及校正曲線,決策分析曲線顯示肌肉分層分析后預(yù)測模型的凈收益明顯高于分層分析前,校準曲線顯示分層分析后預(yù)測模型在實際概率和預(yù)測概率之間具有良好的預(yù)測準確性(圖6、7)。
3討論
既往多項研究已經(jīng)表明肌肉脂肪浸潤對OLT患者的預(yù)后存在一定的潛在影響[13,16,24-25],通過本次回顧性研究發(fā)現(xiàn),肌肉脂肪浸潤在OLT患者中普遍存在,并且在出現(xiàn)術(shù)后并發(fā)癥的患者中,發(fā)生率相對較高。本研究在肌肉脂肪浸潤的基礎(chǔ)上,通過對L3椎體水平全腹壁肌肉進行分層分析后發(fā)現(xiàn),將肌肉內(nèi)部按照不同密度范圍劃分成不同的亞分區(qū),不僅為臨床提供了更多的影像學測量參數(shù),而且還提升了術(shù)后并發(fā)癥預(yù)測模型的效能,相比肌肉分層分析前的預(yù)測模型,LR-CS、RFC-CS、SVM-CS模型的AUC值有了一定的提升,并且通過Delong檢驗證實LR-C和LR-CS模型測試集的AUC存在明顯統(tǒng)計學差異(Plt;0.05),而且在模型靈敏度、特異度等相關(guān)參數(shù)方面均有良好提升。其實,2019年Zhuang等[26]在一項關(guān)于胃癌的研究中就曾提出過將肌肉內(nèi)部劃分成不同的亞分區(qū),這對了解肌肉密度改變對胃癌術(shù)后不良結(jié)局的影響是有價值的。此外,在2020年也有研究提出使用肌肉質(zhì)量圖來展示肌間脂肪區(qū)域、低密度肌肉區(qū)域和正常密度肌肉區(qū)域[27]。本研究通過對肌肉內(nèi)部進行分層分析后發(fā)現(xiàn),該方法在一定程度上彌補了目前肌肉脂肪浸潤評價方式的不足,原因在于目前大多數(shù)研究采用的是Martin等[21]通過最優(yōu)分層方法提出的適用于胃腸道腫瘤患者預(yù)后評價的方法,但是當部分患者腹壁肌肉出現(xiàn)了局部重度脂肪化,而SMRA確處于正常范圍時,該方法就會將其誤判為正常,這與實際情況并不相符合,此時肌肉內(nèi)部分層分析就顯得尤為重要。其次該方法也并不一定適用于OLT患者肌肉脂肪浸潤的評價。目前肺癌[28-29]、卵巢癌[30-31]、壺腹周圍癌[32]、胰腺癌[33]、食管癌及食管胃結(jié)合部癌[34]、彌漫大B細胞淋巴瘤[35]患者肌肉脂肪浸潤的特異性診斷截斷值相繼出現(xiàn),同時有研究根據(jù)研究樣本的中位數(shù)[36]、三分位數(shù)[37]或四分位數(shù)[38]來定義肌肉脂肪浸潤的發(fā)生。雖然本研究通過肌肉分層分析方法建立的肝移植術(shù)后并發(fā)癥預(yù)測模型有著相對良好的效能,但是肌肉脂肪浸潤作為建立模型過程中重要的臨床特征,仍然受到SMRA值的影響。因此,未來應(yīng)該嘗試發(fā)掘適用于肝移植患者肌肉脂肪浸潤評估的方法及SMRA診斷截斷值,繼續(xù)探索更加全面的肌肉內(nèi)部分層分析方法,實現(xiàn)肌肉內(nèi)部的精細管理,為評價患者預(yù)后提供更有價值的影像學參數(shù)。此外,本次研究仍存在一定的局限性,本研究是一項單中心、回顧性研究,并且缺乏外部驗證。另外,本研究中的肌肉相關(guān)參數(shù)是基于二維圖像測量得出的,缺乏肌肉相關(guān)的三維信息,三維圖像中肌肉內(nèi)部的分層分析方法同樣值得進一步研究及探討。
倫理學聲明:本研究方案于2021年1月8日經(jīng)由吉林大學第一醫(yī)院倫理委員會審批,批號:2022-164,臨床試驗注冊機構(gòu)注冊號:ChiCTR2200059026。
利益沖突聲明:本文不存在任何利益沖突。
作者貢獻聲明:石鑫、張蓓負責設(shè)計論文框架,起草論文;石鑫、梁重霄負責實驗操作,研究過程的實施;石鑫、張蓓、梁重霄負責數(shù)據(jù)收集,統(tǒng)計學分析、繪制圖表;王繼萍、石鑫負責論文修改;王繼萍負責擬定寫作思路,指導(dǎo)撰寫文章并最后定稿。
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收稿日期:2024-06-21;錄用日期:2024-07-26
本文編輯:劉曉紅