충수염 의증 청소년 및 젊은 성인에서 2-mSv CT와 기존 선량 CT의 민감도 및 특이도: LOCAT의 사후 하위그룹 분석

학위논문(박사)--서울대학교 대학원 :융합과학기술대학원 융합과학부,2019. 8. 이경호.Introduction: To explore heterogeneity across patient or hospital characteristics in the diagnostic sensitivity and specificity of 2-mSv CT relative to conventional-dose CT (CDCT) in adolescents and young adults with suspected appendicitis. Methods: We used the per-protocol analysis set of a large randomized controlled noninferiority trial conducted between Dec 2013, and Aug 2016, comparing 2-mSv CT and CDCT (typically 7 mSv). The data included 2,773 patients (median age [interquartile range], 28 [21–35] years) and 160 radiologists from 20 hospitals. We tested for heterogeneity in sensitivity and specificity for the diagnosis of appendicitis across predefined subgroups by patient sex, body size, clinical risk scores for appendicitis, time of CT examination (i.e., working hours [typically 08:00–17:00 of working days] vs. after hours), CT machines, radiologists experience, previous site experience in 2-mSv CT, and site practice volume. We drew forest plots and tested for additive or multiplicative treatment-by-subgroup interaction on sensitivity and specificity. Results: The 95% CIs for the between-group differences, particularly for sensitivity, were wide due to small sizes (< 200) for the subgroups of extreme body sizes, high clinical risk score for appendicitis, newer CT machines, hospital with prior experience in 2-mSv CT, and hospitals with small appendectomy volume. Otherwise, the 95% CIs in most subgroups contained the previously reported overall between-group differences as well as null hypothesis value (i.e., 0). There was no significant additive or multiplicative interaction for either sensitivity or specificity. Conclusions: We found no notable subgroup heterogeneity, which implies that 2-mSv CT can replace CDCT in diverse populations. Further studies are needed for the populations for which our subgroups were small.서론: 본 연구는 충수염 의증 청소년 및 젊은 성인에서 기존 CT와 비교하여 2-mSv CT의 진단 민감도 및 특이도에서 환자 또는 병원의 특성에 따른 이질성이 있는지를 탐색하는 연구임. 방법: 본 연구는 2013년 12월에서 2016년 8월 사이에 15–44세의 환자에서 2-mSv CT와 기존 선량 CT (일반적으로 7 mSv)를 비교한 대규모 비열등성 무작위배정 임상시험의 프로토콜 별 분석세트를 사용함. 본 연구에는 20개 병원에서 2,773명의 환자 (중앙값 연령 [사분위수 범위], 28 [21–35]세)가 포함되었으며, 160명의 판독의가 참여함. 환자의 성별, 신체 크기, 충수염에 대한 임상 위험 점수, CT 검사시간 (일과시간 [근무일 기준 오전 8시부터 오후5시] 또는 일과시간 이후), CT 장비, 판독의의 경험정도, 2-mSv CT에 대한 이전 경험 여부, 그리고 병원의 임상규모 등의 사전 정의된 하위 그룹에서 충수염 진단을 위한 민감도 및 특이도의 이질성을 테스트함. 두 군의 차이를 숲그림으로 제시하고, 민감도와 특이도에 대한 덧셈 및 곱셈 상호작용을 테스트함. 결과: 많이 날씬하거나 뚱뚱한 경우, 충수염 염증 반응 점수가 높은 경우, 최신 CT 기기를 사용한 경우, 2-mSV CT 의 이전 경험이 있는 병원, 그리고 충수절제술 규모가 작은 병원의 경우 등 특정 하위 그룹은 작은 크기 (< 200)로 인해 민감도에 대한 95 % 신뢰구간이 넓었음. 그 외, 대부분의 하위 그룹에서 그룹 간 차이에 대한 95 % 신뢰구간은 이전 보고된 전체 그룹 간 차이 및 귀무 가설 값 (즉, 0)을 포함하였음. 2-mSv CT 군과 기존 선량 CT 군 간에 민감도 및 특이도에서 덧셈 또는 곱셈 상호작용을 보이는 하위 그룹은 없었음. 결론: 충수염 의증 청소년과 젊은 성인에서 2-mSv CT와 기존 선량 CT 간에 민감도와 특이도에서 이질성을 보이는 하위그룹은 없었음. 이는 2-mSv CT가 다양한 집단에서 기존 선량 CT를 대체할 수 있음을 의미함. 다만, 본 연구에서 작은 크기를 가진 일부 하위 그룹에 대해서는 추가적인 연구가 필요함.INTRODUCTION 1 Motivations of LOCAT 1 Purposes of LOCAT 3 Motivations of Dissertation Research 4 Purposes of Dissertation Research 5 BACKGROUND 7 Epidemiology of Appendicitis and CT utilization 7 Imaging Utilization 7 Popularity of CT 8 CT Radiation 9 Radiation Dose Level 10 Typical Radiation Dose for Multi-purpose Abdomen CT 10 Typical Radiation Dose for Appendiceal CT 11 Low Doses Explored in Research Settings 12 Carcinogenic Risk Associated with CT Radiation 12 Controversy 13 ALARA Principle 14 Efficacy and Effectiveness of LDCT Compared to CDCT 15 Clinical Outcome 19 Diagnostic Performance 20 Inter-observer Agreement 21 Differentiation between Complicated vs. Uncomplicated Appendicitis 22 Image Quality 24 Visualization of the Appendix 24 Alternative Diagnoses 25 Step-wise Multimodal Diagnostic Approach Incorporating LDCT 27 Patient Subgroups Less Benefited from LDCT 27 Selective Utilization of LDCT 29 Additional Imaging Test(s) Following LDCT 30 Imaging Techniques for LDCT for Suspected Appendicitis 31 Intravenous Contrast Enhancement 31 Contrast-enhancement Phase 31 Enteric Contrast 32 Anatomical Coverage 32 Tube Current 33 Tube Potential 34 Iterative Reconstruction 34 Image Reconstruction Thickness 35 Coronal Reformation 35 Sliding-Slab Averaging Technique 36 Image Interpretation and Reporting for LDCT 37 Diagnostic Criteria for Appendicitis 37 Structured Reporting 38 Other Practical Issues in Implementing LDCT 39 Dedicated Protocol for Appendiceal CT 40 Education for Referring Physicians and Surgeons 41 Education for Radiologists 42 Dose Calibration and Monitoring 43 MATERIALS AND METHODS 47 Study Overview 47 Practice Setting 48 Pre-registration Procedures 48 Study Organization and Site Recruitment 49 Site Activation 50 Patients 51 Eligibility Criteria 54 Clinical Suspicion for Appendicitis 55 The Need for CT Examination 55 Generalizability 56 Representativeness of Study Sample 57 Withdrawal Criteria 58 Randomization 58 Index Test 59 CT Image Acquisition and Archiving 66 Radiation Doses 69 Record of Modulated Radiation Dose 71 Target Median DLP Values for the 2-mSv CT and CDCT groups 71 Calibration of Radiation Doses 72 Estimation of Carcinogenic Risk Associated with CT Examination 74 Image Interpretation 75 Radiologists and CT Reports 76 Radiologist Training 78 Considerations Regarding Technical Advantages over Previous Studies 79 Image Submission 80 Co-intervention 81 Additional Imaging 82 General Treatment Guidelines 82 Follow-up 84 Endpoints in LOCAT 85 Primary Endpoint 86 Secondary Endpoints 86 Considerations for NAR and APR 89 Changes in Endpoints 89 Reference Standards 91 Overview of Reference Standards 91 Definition of Acute Appendicitis 92 Mild or Early Acute Appendicitis 92 Appendiceal Diverticulitis 93 Cases of Delayed Appendectomy 93 Periappendicitis 93 Definition of Appendiceal Perforation 94 Reporting AEs 95 Definition of AE 96 Definition of SAE 97 AE Characteristics 97 Grade 98 Expected/Unexpected AEs 98 Attribution 98 Individual Symptoms vs. Single Diagnosis 99 Who Should Report AEs 99 How to Report AEs 99 Follow-up for AEs 100 Ethical Considerations 100 Ethics and Responsibility 100 Informed Consent Form 101 Data Security and Participant Confidentiality 101 Early Stopping Rules in LOCAT 101 Data Management 102 Case Report Forms 103 Monitoring Participant Accrual 103 Monitoring Data Quality 103 Data and Safety Monitoring Board 105 Statistical Analysis 105 Considerations for Primary Endpoint 105 Analysis Plans 107 Sample Size 108 Sample Size Considerations 108 Final Sample Size 110 Rationale for the Noninferiority Margin 111 Reported NARs Following Preoperative CT 111 Reported NARs in Patients Without Preoperative CT 112 Sample Size Considerations on APR 113 Subgroup Analyses for APR and NAR 114 Subgroup Analyses for Diagnostic Performance 116 RESULTS 119 Patient Characteristics 119 Overall Diagnostic Performance 123 Subgroups of Limited Comparison 123 Between-group Differences for Subgroups 123 Heterogeneity 131 DISCUSSION 132 CONCLUSION 139 REFERENCES 140 APPENDIX 164 Abstract in Korean 176Docto