BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available.
When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to.
The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript.
BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com).
If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 25, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
Somatic Symptom Scale-China (SSS-Ch) study: protocol for measurement and severity evaluation of a self-report version of a somatic symptom questionnaire in a general hospital in China
ForJournal: peerBMJ Open review only
Manuscript ID bmjopen-2018-024290
Article Type: Protocol
Date Submitted by the Author: 28-May-2018
Complete List of Authors: Su, Xuan; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Zhang, Weituo; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Gao, Chuang; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Mao, Jialiang; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Jiang, Meng; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Pu, Jun; Renji Hospital, School of Medicine, Shanghai Jiaotong University
Somatic Symptom Scale-China, somatic symptom disorder, mental http://bmjopen.bmj.com/ Keywords: disorders management
on September 25, 2021 by guest. Protected copyright.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Somatic Symptom Scale-China (SSS-Ch) study: protocol for measurement 4 5 6 and severity evaluation of a self-report version of a somatic symptom 7 8 questionnaire in a general hospital in China 9 10 Xuan Sua1, MD, Weituo Zhanga2, PhD, Chuang Gao, MPH2, Jialiang Mao*1, MD, PhD, Meng 11 12 *1 *1 13 Jiang , MD, PhD, Jun Pu , MD, PhD 14 1 15 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong 16 For peer review only 17 University, Shanghai, China 200127; 18 19 2 Clinical Research Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 20 21 China 200025 22 23 24 25 a 26 Co first author: Xuan Su and Weituo Zhang contribute equally to the paper. 27 28 * Name and address for co correspondence: Meng Jiang, MD, Ph.D., FSCMR; Jialiang Mao, 29 30 MD, Ph.D.; and Jun Pu, MD, Ph.D., FACC. Department of Cardiology, Renji Hospital, 31 32 School of Medicine, Shanghai Jiaotong University, Shanghai, China; 160 Pujian Road,
33 http://bmjopen.bmj.com/ 34 Shanghai, China, 200127. Tel: 086 21 68383447, Fax: 086 21 68383447; Email: 35 36 [email protected]; [email protected] and [email protected] . 37 38 39 40 Word count: 3498
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 ABSTACT 4 5 Aim The current self reporting questionnaires neither sufficiently consider accompanying 6 7 8 anxiety and depression nor are validated for monitoring the treatment efficacy of the patients 9 10 with somatic symptom disorder (SSD). The Somatic Symptom Scale China (SSS Ch) 11 12 questionnaire was developed due to the urgent clinical demand in general hospitals. We 13 14 attempt to determine if this self administered SSS Ch could serve as a timely and practical 15 16 instrument to detectFor SSD andpeer to assess thereview severity of this disorder. only 17 18 19 Methods/Design A prospective diagnostic study conducted at 3 centres. Patients without 20 21 organic disease but presenting with physical discomfort will be recruited and undertake the 22 23 SSS Ch, the Patient Health Questionnaire 15 (PHQ 15), the Patient Health Questionnaire 9 24 25 (PHQ 9) and the Generalized Anxiety Disorder Scale 7 (GAD 7) checklists. An independent 26 27 diagnosis will be made by a primary care physician using the fifth edition of the Diagnostic 28 29 30 and Statistical Manual of Mental Disorders (DSM 5) criterion standards. Patient with SSD 31 32 will be selectively prescribed according to the severity category assessed by physician,
33 http://bmjopen.bmj.com/ 34 selective serotonin reuptake inhibitors or serotonin–norepinephrine reuptake inhibitors. Two , 35 36 6 , and 10 week follow ups will be scheduled for repeating the questionnaires in patient with 37 38 SSD. The primary outcomes will be diagnosis and severity assessment accuracy of SSD. 39 40 Secondary outcomes will be whether the SSS Ch is effective in monitoring treatment efficacy
41 on September 25, 2021 by guest. Protected copyright. 42 43 of SSD in primary care patients, whether the current cut off value needs to be optimized, and 44 45 how often somatic disorder is accompanied by anxiety or depression. 46 47 Ethics and dissemination Ethical approval was provided by the Renji Hospital Human 48 49 Research Ethics Committee, approval number 2015016. The findings of this study will be 50 51 52 disseminated via peer reviewed journals and presented at international conferences. 53 54 55 56 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Strengths and limitations of this study 4 5 1. A strength of this study is that solid validation is achieved. The SSS Ch is designed to be 6 7 8 double verified by both the DSM 5 and treatment efficacy. 9 10 2. It is suitable for Chinese national conditions. 11 12 13 3. 50% of the items in the SSS Ch are designed for depression or anxiety since it is stated in 14 15 the DSM 5 that SSD can be accompanied by depression or anxiety. 16 For peer review only 17 4. The current SSS Ch study is further modified based on the DSM 5 and, for the first time, is 18 19 20 applied for evaluating its clinical utility. 21 22 5. A potential limitation of this study is that our current study only represents the efficacy of 23 24 SSS Ch utility in patients without organic diseases, and the study was designed as a midterm 25 26 investigation with four measurement points, so missing data are to be considered. 27 28 29 Keywords 30 31 32 Somatic Symptom Scale China; somatic symptom disorder; mental disorders management.
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 INTRODUCTION 4 5 One of the most common medical conditions seen in general hospitals is somatic symptom 6 7 1 2 8 disorder (SSD) . SSD refers to symptoms reported by patients that often difficult to explain 9 3 10 after adequate evaluation , and even when significant medical disease is present, the patients’ 11 2 12 symptoms may nonetheless be unrelated to their disease . Cardiac neurosis, irritable bowel 13 14 syndrome, fibromyalgia, and chronic fatigue syndrome are related terms to describe these 15 16 “functional diseases”For in variouspeer clinical review departments, while only “SSD” is the term used in the 17 18 field of psychiatry and psychology (ICD 10, DSM 5)2 4. The disorder has an estimated 19 20 2 21 current prevalence in the general population of 1% to 19% and in general medical practice of
22 5 7 23 16% to 30% . Up to 70 80% of patients choose to visit a general hospital instead of a 24 2 25 psychiatric clinic . The recognition rate is unsatisfactory due to the diagnostic complexity; 26 27 therefore, patients would sustain somatic symptoms without appropriate treatment due to the 28 29 lack of awareness or effective screening instruments for SSD. Patients with somatization had 30 31 approximately twice the outpatient and inpatient medical care utilization and twice the annual 32
33 http://bmjopen.bmj.com/ 34 medical care costs as non somatizing patients. An estimated $256 billion in annual medical
35 1 36 care cost is attributable to the incremental effects of somatization alone . Whereas depression 37 38 and anxiety disorders are widely researched, SSD has been far less studied. Follow up or 39 40 treatment studies of this kind are even scarcer. Hence, it is of great importance for primary
41 on September 25, 2021 by guest. Protected copyright. 42 care physicians to be prepared to, in a timely manner, identify as well as grade symptom 43 44 severity and treat SSD, which can result in high degrees of morbidity, lost productivity, and 45 46 8 9 47 overutilization of medical resources . 48 49 The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5) is 50 51 currently the "gold standard" for the diagnosis of SSD2, with the aim of avoiding the 52 53 omission of patients and assessing the disorder severity. The DSM 5 criteria emphasized that 54 55 56 it is important to evaluate patients in terms of psychology, behaviour and their body 57 58 59 4 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 conditions and then treat the patients according to the severity of the disorder. The DSM 5, 4 5 however, is hard to follow clinically since it depends on qualified and experienced physicians 6 7 with an interview longer than half an hour. It is more clinically practical to detect a disorder 8 9 by self administered questionnaires, where patients can score symptoms according to their 10 11 own condition and severity in a short time. The most available questionnaires are the Patient 12 13 10 11 14 Health Questionnaire 9 (PHQ 9) and the Generalized Anxiety Disorder Scale 7 (GAD 7) . 15 16 The PHQ 9 is usedFor for assessing peer depression, review and the GAD 7 only is focused on anxiety. Both are 17 18 widely used in clinical practice and research, but it remains unknown whether they can be 19 20 used for screening SSD. The Patient Health Questionnaire 15 (PHQ 15)12 and its simplified 21 22 version—the Somatic Symptom Scale 8 (SSS 8)13—were developed in recent years, aiming 23 24 to provide a reference for physicians to detect suspected somatic burden quickly in health 25 26 27 care visits. However, their efficacy for treatment evaluation is unclear. In addition, it is stated 28 29 in the DSM 5 that SSD could be accompanied by depression or anxiety. Approximately 30 31 57.7% of SSD patients had comorbid anxiety or depressive disorder, as reported by Arthur et 32 1 33 al. , but there are just 2 items related to depression on the PHQ 15 and SSS 8 scales. We http://bmjopen.bmj.com/ 34 35 developed a self administered questionnaire, the SSS Ch, that integrates somatic symptoms 36 37 with depression and anxiety items. It is designed to aid in screening for SSD diagnosis, SSD 38 39 40 burden assessment and follow up monitoring.
41 on September 25, 2021 by guest. Protected copyright. 42 The Somatic Symptom Scale China (SSS Ch) was developed based on the DSM 5 to 43 44 investigate suspected SSD. It is an abbreviated 20 item version of somatic symptoms that can 45 46 47 be entirely self administered by the patient. The SSS Ch is designed to assess the presence 48 49 and severity of common somatic symptoms. Our previous study validated its reliability and 50 14 51 validity . Items in the scale include somatic symptoms (50%, 10/20 items), anxiety (20%, 52 53 4/20 items), depression (20%, 4/20 items), and anxiety and depression (10%, 2/20 items). 54 55 Unlike the severity category from the DSM 5, the severity assessment of the SSS Ch is based 56 57 58 59 5 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 on both individual items and the general evaluation. In addition, it is specified in each item 4 5 and avoids certain questions to accommodate Chinese culture. The SSS Ch is designed to be 6 7 administered to outpatients in internal medicine. It aims to establish a more accessible and 8 9 affordable way to increase the health of patients. 10 11 12 Study objectives and research questions 13 14 Primary objectives 15 16 For peer review only 17 The primary objectives of this study are to test the clinical utility: (1) Diagnostic accuracy: 18 19 we expect that with a DSM 5 referenced physician diagnosis as the gold standard, somatic 20 21 symptom disorder assessed by the SSS Ch will be as accurate as the current PHQ 15 22 23 24 evaluation. (2) Somatic burden assessment: we expect to use the SSS Ch for measuring SSD 25 26 severity. 27 28 Secondary objectives 29 30 31 Secondary objectives include the following: (1) We intend to observe the characteristics of 32
33 the SSS Ch for its efficacy in monitoring the treatment effect in primary care patients. In http://bmjopen.bmj.com/ 34 35 detail, we intend to explore whether the SSS Ch is non inferior compared to the PHQ 15, 36 37 PHQ 9, or GAD 7 and to determine in which aspect the SSS Ch has an advantage. (2) We 38 39 intend to evaluate whether the current cut off value needs to be optimized. (3) We aim to 40
41 on September 25, 2021 by guest. Protected copyright. 42 determine how often SSD is accompanied by anxiety or depression or in which circumstances 43 44 SSD is accompanied by anxiety or depression. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 6 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 METHODS 4 5 Study overview 6 7 8 This study will use a prospective interventional diagnostic design and will be conducted in 9 10 the internal medicine department at 3 sites of a tertiary general hospital in Shanghai, China. 11 12 This study protocol was approved by the ethics committees of Renji Hospital, and written 13 14 informed consent will be obtained from all study participants. Clinical trial registration can be 15 16 For peer review only 17 found at https://register.clinicaltrials.gov/, and the registration number is NCT03513185. 18 19 Particular attention will be paid to ensure the appropriate storage of this study. Patient and 20 21 reviewer confidentiality will be maintained, and no identifying features will be published. 22 23 15 24 The protocol development is adhered to the EMA guideline for diagnosis study . 25 26 Description of the SSS-Ch and Assessment of Severity 27 28 29 The SSS Ch is a somatic symptom scale (Figure 1) we derived from the DSM 5. It queries 30 31 approximately 10 somatic clusters that account for 50% of the physical complaints (1 item 32
33 per body system). Another 50% composes the anxiety and depression items (anxiety, 20% http://bmjopen.bmj.com/ 34 35 (4/20); depression, 20% (4/20); anxiety and depression, 10%). Subjects are asked the 36 37 following: “Since you have felt unwell, how often have you been bothered by any of the 38 39 following problems?” For scoring, subjects are asked to rate the severity of each symptom as 40
41 on September 25, 2021 by guest. Protected copyright. 42 1 (“does not exist”), 2 (“bearable”), 3 (“influences daily work to some extent”) or 4 43 44 (“unbearable”). Thus, in determining the SSS Ch score, each individual symptom is coded as 45 46 1 4, and the total score ranges from 20 to 80. Severity categories are assessed in accordance 47 48 with SSS Ch percentile ranks. SSS Ch scores within cut off points of normal range 39, 40 49 50 59, and ≥60 represent mild, moderate, and severe SSD. The selection of these cut off values 51 52 takes into account the results of our previous study (a reliability and validity study of the 53 54 4 55 early version of SSS Ch) and clinical experience. 56 57 58 59 7 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Study Design 4 5 Consecutive outpatients complaining about physical discomfort will first undergo 6 7 8 corresponding examinations. For patients with no systemic disease that can account for their 9 10 discomfort, the patient will be considered to have a probability of somatic disorder. Patients 11 12 will then be transferred to a specialist clinic for suspected SSD. Before seeing their 13 14 physicians, patients will undertake the SSS Ch, the PHQ 15, the PHQ 9 and the GAD 7 15 16 questionnaires, For and non clinical peer research review assistants will only collect the questionnaires and 17 18 determine the scores. A physician who is blind to the results of the SSS Ch will separately 19 20 21 evaluate the patient and will give prescriptions according to the DSM 5 severity category. 22 23 Two , 6 , 10 week follow ups will be scheduled for repeating the questionnaires for patient 24 25 with medications. A 20 Item Short Form Health Survey (SF 20) will be conducted as the 26 27 healthy reference during follow up. A study flow chart is shown in Figure 2. 28 29 30 Participants and procedure 31 32 Inclusion criteria
33 http://bmjopen.bmj.com/ 34 35 (1) patients aged 18 80 years old; (2) patients who have no previous diagnosis of somatic 36 37 disease; (3) patients without systemic disease that can account the physical discomfort; (4) 38 39 patients who agree to complete the checklists and undergo assessment by a physician. 40
41 on September 25, 2021 by guest. Protected copyright. 42 Exclusion criteria 43 44 (1) patients who have lost their self assessed abilities or refuse to participate; (2) patients who 45 46 have been previously confirmed to have serious mental disorders, mental retardation or 47 48 49 dementia; (3) patients who are taking anti anxiety agents or anti depression agents; (4) 50 51 patients who are unable to complete at least 1 follow up. 52 53 Blinding 54 55 56 57 58 59 8 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 After a patient with suspected SSD is transferred to the specialist clinic, the patient will first 4 5 complete the questionnaires in a separate room; then, an initial consultation will be blindly 6 7 conducted by a physician who has been qualified as a National Psychological counsellor. An 8 9 independent diagnosis and severity category will be assigned by the physician using the 10 11 DSM 5 criterion standard. The time of the self report scale and the physician assessment will 12 13 14 be separately recorded. 15 16 Intervention For peer review only 17 18 19 Medications will be given according to the physician’s evaluation. Anti anxiety treatment or 20 21 anti depression treatment will be selectively administered according to the severity of 22 23 somatic symptom burden. Generally, members of the thioxanthene class, such as Deanxit, 24 25 that are used as mild, selective serotonin reuptake inhibitors (SSRIs) are applied for moderate 26 27 symptoms, and serotonin norepinephrine reuptake inhibitors (SNRIs) are applied for severe 28 29 30 symptoms based on the DSM 5, with the serotonin antagonist and reuptake inhibitor (SARI) 31 32 class prescribed if sleeping problems exist.
33 http://bmjopen.bmj.com/ 34 Follow-up 35 36 37 A face to face interview will be scheduled at 2, 6, and 10 weeks for patients taking 38 39 medication in order to follow up using the SSS Ch, PHQ 15, PHQ 9 and GAD 7 40
41 questionnaires. An SF 20 survey will be conducted as the healthy reference to evaluate on September 25, 2021 by guest. Protected copyright. 42 43 patient status. 44 45 46 Outcome measures 47 48 49 Reliability & Validity 50 51 Reliability will be measured by the Cronbach’s alpha. A randomized sample of 52 53 approximately 100 participants will be asked to complete the checklists 1 week after the 54 55 initial completion to analyse the test retest reliability. 56 57 58 59 9 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Criterion validity will be calculated by the correlations of the diagnostic results and severity 4 5 assessments of somatic symptoms between the SSS Ch and the gold standard. 6 7 8 Construct validity will be tested by confirmatory factorial analysis comparing corresponding 9 10 factors with the PHQ 15, PHQ 9 and GAD 7. (The SSS Ch consists of 10 questions for 11 12 somatic symptom, 4 for depression, 4 for anxiety, and 2 for depression anxiety.) 13 14 Diagnostic performance 15 16 For peer review only 17 Diagnostic accuracy of a questionnaire is measured by the AUC of an ROC curve, the 18 19 sensitivity / specificity under given cut off values, and the positive / negative predictive 20 21 values in the study population, referring to the physician diagnosis as the gold standard. 22 23 24 Accuracy of severity assessment of a questionnaire is measured by the Spearman correlation 25 26 between the questionnaire score and the physician’s severity assessment. 27 28 29 Other Clinical utilities 30 31 Convenience in clinical practice is measured by the average time taken to complete each 32
33 questionnaire or receive a diagnosis from a physician. http://bmjopen.bmj.com/ 34 35 36 Clinical utility in monitoring treatment efficacy of SSD in primary care patients is measured 37 38 by correlation with the reference SF 20 during follow up visits. 39 40 Sample size calculation
41 on September 25, 2021 by guest. Protected copyright. 42 43 The calculation considers the sample sizes for both the comparison of SSD diagnosis and the 44 45 severity assessment, whichever one was larger. In the pilot study, the prevalence of SSD was 46 47 48 76.9% in the study population who were referred to the special clinics, the AUC of the ROC 49 50 curve for PHQ15 was 0.88, and the correlation of the PHQ15 score with the physician's 51 52 diagnosis was 0.77 (95%CI: 0.43, 0.92). The correlation of SSS CH and PHQ15 scores was 53 54 set to 0.6. With a non inferiority margin of 0.05, α=0.025, and β=0.8, the sample size for SSD 55 56 diagnosis was 852. With a non inferiority margin of 0.1, α=0.025, and β=0.8, the sample size 57 58 59 10 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 for severity assessment was 579. Therefore, as the overall sample size of this study was 4 5 N=852 with SSD positive N+=655, and SSD negative N =197, both the positive and negative 6 7 sample size requirements were met. 8 9 10 Statistical analysis 11 12 We will compute the mean (SD) questionnaire scores and the number of patients (%) in each 13 14 diagnostic category as descriptive statistics. 15 16 For peer review only 17 Reliability will be measured using Cronbach’s α. The criterion validity will be measured by 18 19 the kappa coefficient of diagnosis and the Kendall tau b of severity assessment. Construct 20 21 validity will be tested using confirmatory factor analyses. 22 23 24 The primary analysis of the diagnostic performance will consist of two comparisons using 25 26 Bonferroni correction: (1) the non inferior comparison of SSS Ch with PHQ 15 in the SSD 27 28 diagnostic accuracy as measured by the AUC of ROC with =0.05, α=0.025 in the whole 29 30 31 study population; (2) the non inferior comparison of SSS Ch with PHQ 15 in the SSD 32 severity assessment measured by Spearman’s correlation with =0.1, α=0.025 in the
33 http://bmjopen.bmj.com/ 34 35 population with a confirmed SSD diagnosis. Both comparisons refer to the physician’s 36 37 diagnosis as the gold standard. If either non inferior is met, the corresponding superior will 38 39 be tested. 40
41 on September 25, 2021 by guest. Protected copyright. 42 As a secondary analysis, the sensitivity, specificity, and positive and negative predictive 43 44 values will also be reported. We will further optimize and validate the cut off values of the 45 46 SSS Ch. In addition, we will compare the time to complete each questionnaire and be 47 48 diagnosed by a physician and will compare the correlation between questionnaire scores and 49 50 51 the quality of life (SF 20) in the follow up data. 52 53 Sensitivity analysis will be conducted by comparing the analysis results with and without 54 55 sex and age adjustment. Missing values will be imputed with a state of the art technique16. 56 57 58 59 11 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Patient and public involvement statement 4 5 Development of the research question 6 7 8 Up to 70 80% of patients with SSD visit a general hospital instead of a psychiatric clinic. The 9 10 current self reporting questionnaires neither sufficiently consider accompanying anxiety and 11 12 depression nor are validated for monitoring the treatment efficacy of such groups. The SSS 13 14 Ch questionnaire was developed due to the urgent clinical demand in general hospitals. 15 16 For peer review only 17 Outcome measures informed by patients’ priorities, experience, and preferences. 18 19 20 Research assistant will be dedicated to help patient understand the questions. We also take 21 22 care of the patients’ comfort in completing the questionnaires including the set of 23 24 questionnaires needed, special clinic prepared, patient privacy protection. 25 26 Patients involvement in the design of this study 27 28 29 Patients were got involved in the following aspects in the design of this study: the 30 31 understandability, acceptability of the language of the questionnaires, the number of 32
33 questionnaires, the acceptable time to complete the questionnaires, the follow up method, the http://bmjopen.bmj.com/ 34 35 36 manner of notification of the disease condition, the manner of feedback during the research 37 38 process. 39 40 Patient involvement in the recruitment and conduct of the study
41 on September 25, 2021 by guest. Protected copyright. 42 43 Patient are allowed to recommend other potential study candidates. We also encourage 44 45 patients to give feedback on issues in the early and mid term phase of the study. 46 47 48 Study dissemination to study participants 49 50 Patients will be informed of the results immediately after the physician consultant and the 51 52 questionnaire are completed. Patients will communicate with the doctor throughout the 53 54 55 56 57 58 59 12 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 diagnosis and treatment. The study results will be written and submitted for publication in 4 5 peer reviewed journals. Patients can get the published article for personal use. 6 7 8 Current status 9 10 The first study participant was enrolled in November 2017. In May 2018, patient recruitment 11 12 was not completed. 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 13 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 DISCUSSION 4 5 In this study protocol, we describe a diagnostic study design that evaluates the efficacy of a 6 7 8 newly developed somatic symptom scale from China for patients with suspected somatic 9 10 diseases, which might be applied as a first line instrument for screening and monitoring the 11 12 treatment efficacy in individual outpatient consultations. We expect that a study physician 13 14 will benefit from the SSS Ch on a clinically significant level in a timely manner and that the 15 16 participants willFor benefit from peer improving review their awareness and only self monitoring of the disease. 17 18 Moreover, we will examine the characteristics of the SSS Ch compared with other somatic 19 20 21 symptom questionnaires. 22 23 Our SSS Ch is designed as a “one stop shop” tool that combines somatic items with mental 24 25 disorder items. This is consistent with the suggestion in the DSM 5 that somatic symptoms 26 27 are likely accompanied by depression and anxiety1. Somatic symptoms may interleave with 28 29 30 mental items, and the mental symptoms may be triggered differently from conventional 31 32 mental diseases in this group. Clinically, it is not easy to clearly separate body from mental
33 http://bmjopen.bmj.com/ 34 status, and each item’s significance is unknown. We caution that 50% of mental items have 35 36 the possibility of increasing the incidence of SSD, and a subgroup score with somatic 37 38 symptom items alone is used for this appraisal. 39 40 This trial had some limitations. First, SSD can be accompanied by diagnosed medical 41 on September 25, 2021 by guest. Protected copyright. 42 43 disorders. Our current study, however, only represents the efficacy of SSS Ch utility in 44 45 patients without organic diseases. With this in mind, further application of the SSS Ch in 46 47 specific diseases should be separately investigated. Second, the study was designed as a mid 48 49 term investigation with four measurement points, so missing data are to be considered. 50 51 52 Referring to the fact that only 16% of patients in the PRIME MD study (primary care 53 17 54 evaluation of mental disorders study) were involved in follow up , we estimate that a high 55 56 rate of missing data will occur in patients with SSD. Fortunately, each subject in our study 57 58 59 14 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 will undergo the same set of questionnaires for the entire scale, so the missing samples who 4 5 are lost to follow up will not differ among the groups and therefore will not produce 6 7 significant bias and will not affect our assessment. 8 9 10 The study had several strengths. First, solid validation is achieved. The SSS Ch is designed 11 12 to be double verified by both the DSM 5 and treatment efficacy. Second, it is suitable for 13 14 national conditions. Considering Chinese culture, we modified some items such as sexual 15 16 discomfort into For“discomfort peer at the below review region”, and each onlyitem was detailed for subjects to 17 18 choose in order not to miss a patient’s ailment or promote sensitivity. Third, 50% of the items 19 20 21 in the SSS Ch are designed for depression or anxiety since it is stated in the DSM 5 that SSD 22 23 can be accompanied by depression or anxiety. Finally, our previous study has shown the 24 14 25 reliability and factorial validity of the SSS Ch by utilizing an early version of SSS Ch . The 26 27 current study is further modified based on the DSM 5 and, for the first time, is applied for 28 29 evaluating its clinical utility. 30 31 32 This study will help to clarify whether the developed SSS Ch score is an effective tool for
33 http://bmjopen.bmj.com/ 34 rapid screening and assessment of severity in patients with suspected SSD in a general 35 36 hospital clinic and for convenient follow up. If the SSS Ch turns out to be effective, it can be 37 38 implemented as a first line screen and follow up option for outpatient use to provide 39 40 personalized information to consulting physician in a timely manner. The study results will
41 on September 25, 2021 by guest. Protected copyright. 42 43 contribute to better outpatient care for SSD. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 15 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Acknowledgements: We thank for the contribution of all the patients to participate and give 4 5 us advises throughout the study design and conduct. 6 7 Conflict of interests: The authors declare that they have no competing interests. 8 9 Ethics approval: Ethical approval was provided by the Renji Hospital Human Research 10 11 Ethics Committee, approval number 2015016. 12 13 14 Consent for publication: All participants provided written informed consent. 15 16 Authors' contributionsFor: XS:peer design and review conduction of study, only acquisition of data, analysis 17 18 and interpretation of data, drafting the manuscript. WTZ: analysis, statistics and interpretation 19 20 of data, drafting the manuscript. CG: analysis, statistics and interpretation of data. JLM: 21 22 made substantial contributions to conception, design and interpretation of data. Revising it 23 24 critically for important intellectual content. MJ: made substantial contributions to conception, 25 26 27 design and interpretation of data. Revising it critically for important intellectual content. JP: 28 29 made substantial contributions to conception, design and interpretation of data. 30 31 Funding: This work was supported by the National Science Fund for Distinguished Young 32
33 Scholars(81625002); National Natural Science Foundation of China(81470391, 81470389); http://bmjopen.bmj.com/ 34 35 Shanghai Outstanding Academic Leaders Program(18XD1402400); Shanghai Municipal 36 37 Education Commission Gaofeng Clinical Medicine Grant Support(20152209 and 38 39 40 20172014); Shanghai Science and Technology Committee(15411963600); Shanghai
41 on September 25, 2021 by guest. Protected copyright. 42 ShenKang Hospital Development Center(16CR3020A and 16CR3034A). 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 16 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 REFERENCES 4 5 1. Barsky AJ, Orav EJ, Bates DW. Somatization increases medical utilization and costs 6 7 8 independent of psychiatric and medical comorbidity. Archives of general psychiatry 9 10 2005;62(8):903 10. doi: 10.1001/archpsyc.62.8.903 [published Online First: 2005/08/03] 11 12 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 13 14 Fifth Edition (DSM 5). Arlington, VA: American Psychiatric Association Publishing 15 16 2013. For peer review only 17 18 3. Barsky AJ. Assessing somatic symptoms in clinical practice. JAMA Intern Med 19 20 21 2014;174(3):407 8. doi: 10.1001/jamainternmed.2013.12177 22 23 4. Organization WH. The ICD 10 Classification of Mental and Behavioural Disorders: 24 25 Clinical Description and Diagnostic Guidelines: WHO 1993. 26 27 5. de Waal MW, Arnold IA, Eekhof JA, et al. Somatoform disorders in general practice: 28 29 prevalence, functional impairment and comorbidity with anxiety and depressive disorders. 30 31 British Journal of Psychiatry the Journal of Mental Science 2004;184(12):470. 32
33 http://bmjopen.bmj.com/ 34 6. Fink P, Hansen MS, Oxhøj ML. The prevalence of somatoform disorders among internal 35 36 medical inpatients. Journal of Psychosomatic Research 2004;56(4):413. 37 38 7. Fink P, Sorensen L, Engberg M, et al. Somatization in primary care. Prevalence, health 39 40 care utilization, and general practitioner recognition. Psychosomatics 1999;40(4):330 8.
41 on September 25, 2021 by guest. Protected copyright. 42 doi: 10.1016/s0033 3182(99)71228 4 [published Online First: 1999/07/14] 43 44 8. Jr SG. The course of somatization and its effects on utilization of health care resources. 45 46 47 Psychosomatics 1994;35(3):263. 48 49 9. Hahn SR, Kroenke K, Spitzer RL, et al. The difficult patient: prevalence, psychopathology, 50 51 and functional impairment. Journal of General Internal Medicine 1996;11(1):1. 52 53 10. Kroenke K, Spitzer RL, Williams JB. The PHQ 9: validity of a brief depression severity 54 55 measure. Journal of General Internal Medicine 2001;16(9):606. 56 57 58 59 17 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 11. Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized 4 5 anxiety disorder: the GAD 7. Archives of Internal Medicine 2006;166(10):1092 97. 6 7 12. Kroenke K, Spitzer RL, Williams JB. The PHQ 15: validity of a new measure for 8 9 evaluating the severity of somatic symptoms. Psychosomatic Medicine 2002;64(2):258 66. 10 11 13. Gierk B, Kohlmann S, Kroenke K, et al. The somatic symptom scale 8 (SSS 8): a brief 12 13 14 measure of somatic symptom burden. Jama Internal Medicine 2014;174(3):399. 15 16 14. Qi Z, JialiangFor M, Chunbo peer L, et al.review Developing of somaticonly self rating scale and its 17 18 reliability and validity. Chinese Journal of Behavioral Medicine and Brain Science 19 20 2010;19(9):847 9. 21 22 15. European Medicines Agency. Pre authorisation Evaluation of Medicines for Human Use: 23 24 Guideline on clinical evaluation of diagnostic agents. 25 26 27 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/W 28 29 C500003584.pdf. 30 31 16. Myers TA. Goodbye, Listwise Deletion: Presenting Hot Deck Imputation as an Easy and 32
33 Effective Tool for Handling Missing Data. Communication Methods & Measures http://bmjopen.bmj.com/ 34 35 2011;5(4):297 310. 36 37 17. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self report version of 38 39 40 PRIME MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders.
41 on September 25, 2021 by guest. Protected copyright. 42 Patient Health Questionnaire. Jama 1999;282(18):1737 44. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 18 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 Figure Legends 4 5 Figure 1 The Somatic Symptom Scale China (SSS Ch). 6 7 8 Figure 2 Study flow. SSS Ch the Somatic Symptom Scale China; PHQ 15 the Patient Health 9 10 Questionnaire 15; PHQ 9 the Patient Health Questionnaire 9; GAD 7 the Generalized 11 12 Anxiety Disorder Scale 7; SF 20 the 20 Item Short Form Health Survey; SSD Somatic 13 14 Symptom Disorder. 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 19 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 The Somatic Symptom Scale-China (SSS-Ch). 46 47 215x279mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 Study flow. SSS-Ch the Somatic Symptom Scale-China; PHQ-15 the Patient Health Questionnaire-15; PHQ-9 25 the Patient Health Questionnaire-9; GAD-7 the Generalized Anxiety Disorder Scale-7; SF-20 the 20-Item 26 Short Form Health Survey; SSD Somatic Symptom Disorder. 27 338x178mm (300 x 300 DPI) 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
Research Protocol for a Diagnostic Study: Identifying and Measuring the Severity of Somatic Symptom Disorder Using the Self-reported Somatic Symptom Scale-China (SSS-Ch) ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024290.R1
Article Type: Protocol
Date Submitted by the 22-Nov-2018 Author:
Complete List of Authors: Mao, Jialiang; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Zhang, Weituo; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Su, Xuan; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Gao, Chuang; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Chen, Bingxu; School of Medicine, Shanghai Jiao Tong University Feng, Zehao; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Jiang, Meng; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology http://bmjopen.bmj.com/ Pu, Jun; Renji Hospital, School of Medicine, Shanghai Jiaotong University
Primary Subject Mental health Heading:
Secondary Subject Heading: Research methods
Somatic Symptom Scale-China, somatic symptom disorder, mental Keywords: disorders management on September 25, 2021 by guest. Protected copyright.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 27 BMJ Open
1 2 3 1 Research Protocol for a Diagnostic Study: Identifying and Measuring the Severity of BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Somatic Symptom Disorder Using the Self-reported Somatic Symptom Scale-China 7 8 3 (SSS-Ch) 9 10 11 4 12 13 14 5 Jialiang Maoa1, MD, PhD, Weituo Zhanga2, PhD, Xuan Su1, MD, Chuang Gao2, MPH, 15 16 6 Bingxu Chen3, MD, Zehao Feng1, MD, Meng Jiang*1, MD, PhD, Jun Pu*1, MD, PhD 17 18 For peer review only 1 19 7 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 20 21 8 University, Shanghai, China 200127 22 23 9 2 Clinical Research Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 24 25 10 China 200025 26 27 3 28 11 School of Medicine, Shanghai Jiao Tong University, Shanghai, China 200025 29 30 12 31 32 13 a Co-first author: Jialiang Mao and Weituo Zhang contributed equally to the paper. 33 34 35 14 * Names and addresses for correspondence: Meng Jiang, MD, PhD, FSCMR; Jun Pu, MD, 36 37 15 PhD, FACC; Department of Cardiology, Renji Hospital, School of Medicine, Shanghai http://bmjopen.bmj.com/ 38 39 16 Jiaotong University, Shanghai, China; 160 Pujian Road, Shanghai, China, 200127. Tel: 086- 40 41 42 17 21-68383447, Fax: 086-21-68383447; Email: [email protected]; 43 44 18 [email protected]. 45 on September 25, 2021 by guest. Protected copyright. 46 19 47 48 20 Word count: 4925 49 50 51 52 53 54 55 56 57 58 59 60 1 Meng Jiang and Jun Pu contributed equally to this paper.
1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 27
1 2 3 1 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Aim The recognition rate of somatic symptom disorder (SSD) in general hospitals is 7 8 3 unsatisfactory. The current self-reported questionnaires do not sufficiently consider both 9 10 11 4 physical and psychological symptoms and are not validated for monitoring treatment efficacy 12 13 5 in patients with SSD. The Somatic Symptom Scale-China (SSS-Ch) questionnaire was 14 15 6 developed due to the urgent clinical demand. The aim of this research is to validate the self- 16 17 7 18 reported SSS-Ch asFor a timely peer and practical review instrument toonly identify SSD and to assess the 19 20 8 severity of this disorder. 21 22 23 9 Methods and Analysis At least 852 patients without organic disease but presenting with 24 25 10 physical discomfort will be recruited at a general hospital. Each patient will undergo a DSM- 26 27 11 5-guided physician diagnosis, including disease identification and severity assessment, as a 28 29 30 12 reference standard. This research will utilize the SSS-Ch to evaluate its diagnostic 31 32 13 performance in SSD compared to that of the Patient Health Questionnaire-15 (PHQ-15) and 33 34 14 other SSD-related questionnaires. Statistical tests for the area under the curve (AUC) of the 35 36 37 15 receiver operating curve (ROC) and Spearman’s correlation will be used to compare the http://bmjopen.bmj.com/ 38 39 16 accuracy of the SSD identification and severity assessment respectively. In addition to this 40 41 17 standard diagnostic study, we will conduct follow-up investigations to explore the 42 43 44 18 characteristics of the SSS-Ch in monitoring treatment effects. 45 on September 25, 2021 by guest. Protected copyright. 46 19 47 48 20 49 50 51 21 Ethics and Dissemination Ethical approval was provided by the Renji Hospital Human 52 53 22 Research Ethics Committee, approval number 2015016. The findings of this study will be 54 55 23 disseminated via peer-reviewed journals and presented at international conferences. 56 57 58 24 Trial registration number: NCT03513185 59 60
2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 27 BMJ Open
1 2 3 1 Strengths and limitations of this study BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 1. First, we introduce a tool to facilitate daily clinical work. The tool provides clinicians 7 8 3 with an easy-to-use questionnaire that can be completed quickly and combines both 9 10 11 4 somatic and psychological features to improve physicians’ comfort level in screening 12 13 5 suspected SSD patients and referring them to specific doctors. 14 15 16 6 2. Second, our previous study has shown the reliability and factorial validity of the SSS- 17 18 7 Ch by utilizingFor an early peer version reviewof the scale. The onlycurrent study further modifies the 19 20 8 SSS-Ch based on the DSM-5 and, for the first time, is applied to evaluate its clinical 21 22 23 9 utility. 24 25 10 3. Third, patients will benefit by improving their awareness of the disease and their 26 27 28 11 ability to self-monitor their symptoms. 29 30 12 4. A potential limitation of this study is that it represents the efficacy of the SSS-Ch only 31 32 33 13 in patients without organic disease. Therefore, further application of the SSS-Ch in 34 35 14 patients with specific diseases should be separately investigated. 36 37 http://bmjopen.bmj.com/ 38 15 5. Since only patients without a positive physical examination will be referred to the 39 40 16 special clinic, a referral bias exists due to the nature of our clinic. Moreover, the 41 42 17 epidemiology of health care facilities is different from that of general hospitals; 43 44 18 therefore, the diagnostic accuracy in a health care sample needs additional 45 on September 25, 2021 by guest. Protected copyright. 46 47 19 investigation. 48 49 20 6. The potential of monitoring the treatment effect will be affected by loss to follow-up 50 51 52 21 bias due to the unpredictable pattern of loss to follow-up. 53 54 22 55 56 57 23 Keywords 58 59 60 24 Somatic Symptom Scale-China; somatic symptom disorder; mental disorders management
3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 27
1 2 3 1 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 One of the common medical conditions observed in general hospitals is somatic symptom 7 8 3 disorder (SSD) and related disorders1 2. SSD refers to symptoms that are often difficult to 9 10 3 11 4 explain after adequate evaluation ; even when significant medical disease is present, the 12 13 5 patients’ symptoms may nonetheless be unrelated to their disease2. Diagnosis of SSD 14 15 6 emphasizes the existence of positive symptoms and signs (one or multiple somatic symptoms 16 17 7 plus abnormal thoughts, feelings, and behaviours in response to these symptoms)2. The 18 For peer review only 19 20 8 disorder has an estimated current prevalence in the general population of 5-7%2. Individuals 21 22 9 with somatic symptoms are commonly encountered in general hospitals and primary care as 23 24 10 well as in psychiatric and other mental health settings2. The recognition rate of SSD is 25 26 27 11 unsatisfactory due to the diagnostic complexity, and some physicians may not feel 28 29 12 sufficiently trained to evaluate patients with suspected SSD; thus, SSD could be 30 31 13 underdiagnosed in routine care. Therefore, patients may sustain somatic symptoms without 32 33 34 14 appropriate treatment due to the lack of awareness of SSD. Patients with somatization had 35 36 15 approximately twice as much outpatient and inpatient medical care utilization and annual 37 http://bmjopen.bmj.com/ 38 16 medical care costs as patients without somatization. An estimated $256 billion in annual 39 40 17 1 41 medical care costs is attributable to the incremental effects of somatization alone . Whereas 42 43 18 depression and anxiety disorders are widely researched, SSD has been far less studied. 44 45 19 Follow-up or treatment studies of this disorder are even scarcer. Hence, it is highly important on September 25, 2021 by guest. Protected copyright. 46 47 20 that physicians be prepared to identify SSD, grade the symptom severity and treat it in a 48 49 50 21 timely manner; failure to do so can result in high degrees of morbidity, lost productivity, and 51 52 22 overutilization of medical resources4 5. 53 54 23 The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is 55 56 2 57 24 currently widely used for the diagnosis of SSD (see Supplementary Figure 1 for detailed 58 59 25 criteria) with the aim of identifying patients and assessing the severity of the disorder. The 60
4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 27 BMJ Open
1 2 3 1 DSM-5 criteria replace the DSM-IV criteria for somatization disorder, undifferentiated BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 6 2 somatoform disorder and pain disorder , and they emphasize that it is important to evaluate 7 8 3 patients in terms of their psychology, behaviour and physical condition altogether and then 9 10 4 treat the patients according to the severity of the disorder. They also incorporate illness 11 12 5 anxiety disorder. Differences in medical care across cultures affect the management of these 13 14 15 6 somatic symptoms. Individuals in China usually refuse to receive psychological counselling. 16 17 7 Thus, in general medical hospitals, non-psychiatric physicians must face more patients with 18 For peer review only 19 8 psychological symptoms. The DSM-5, however, is difficult to follow clinically since it 20 21 6 22 9 depends on qualified and experienced physicians conducting an interview . Moreover, the 23 24 10 fact that anxiety and depressive disorder are often associated with SSD in medical settings (in 25 26 11 approximately 57.7% of SSD patients)1 adds severity and complexity to the somatic 27 28 29 12 components, which makes clinicians feel less confident in dealing with such individuals. It is 30 31 13 more clinically practical to detect a disorder by self-administered questionnaires, where 32 33 14 patients can score the symptoms related to their own condition and severity in a short time. A 34 35 15 series of studies has focused on this issue, using various self-reported questionnaires asking 36 37 http://bmjopen.bmj.com/ 38 16 about either physical or psychological symptoms to screen for SSD7-12. Laferton et al. used 39 40 17 the Patient Health Questionnaire 15-item somatic scale (PHQ-15), the Whiteley Index-7 and 41 42 18 the Scale for the Assessment of Illness Behavior questionnaires to identify SSD7. The 43 44 45 19 Somatic Symptom Scale-8 and Somatic Symptom Scale-12 have been used to assess the on September 25, 2021 by guest. Protected copyright. 46 47 20 validity and reliability of somatic symptoms and the psychological symptoms of SSD, 48 49 21 respectively8-11. Tu et al. have reported using the Whiteley Index-7 to screen for SSD12. 50 51 52 22 Based on the published studies, we aim to develop a self-administered questionnaire to 53 54 23 provide a more comprehensive reflection of the true clinical picture than can be achieved by 55 56 57 24 assessing the somatic complaints alone. Our Somatic Symptom Scale-China (SSS-Ch) 58 59 25 integrates somatic symptoms with depression and anxiety items. It incorporates affective, 60
5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 27
1 2 3 1 cognitive, and behavioural components. It is designed to be used in general medical facilities BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 and to provide a tool for clinicians to quickly detect suspected somatic burden. It aims to 7 8 3 establish a more accessible and time-saving way to assess the status of subjects. 9 10 11 4 The SSS-Ch questionnaire was developed based on the DSM-5. Additionally, it 12 13 5 simultaneously evaluates depression and anxiety. It introduces illness anxiety disorder, which 14 15 6 was previously not included in the DSM-IV. For the first time, an organ-based evaluation is 16 17 7 used. The questionnaire is an abbreviated 20-item version that can be entirely self- 18 For peer review only 19 20 8 administered by the patient. The SSS-Ch is designed to assess the presence and severity of 21 22 9 the symptoms. Our previous study validated its reliability and validity13. Briefly, in that 23 24 10 study, the SSS-Ch was composed of 4 dimensions: physical disorder, anxiety disorder, 25 26 27 11 depression disorder, and anxiety and depression disorder. The test-retest reliability was 0.9. 28 29 12 The correlation coefficient between each dimension and the total was between 0.76 and 0.88, 30 31 13 and the correlation coefficient within dimensions was 0.56-0.70. Items in the scale assess 32 33 34 14 somatic symptoms (50%, 10/20 items), anxiety (20%, 4/20 items), depression (20%, 4/20 35 36 15 items), and anxiety and depression (10%, 2/20 items). 37 http://bmjopen.bmj.com/ 38 39 16 Study objectives and research questions 40 41 17 Primary objective 42 43 44 18 The primary objective of this study is to test two types of diagnostic accuracy with a DSM-5- 45 on September 25, 2021 by guest. Protected copyright. 46 19 guided physician diagnosis as the reference standard: (1) the accuracy of the SSS-Ch 47 48 49 20 compared to the PHQ-15 for identifying SSD and (2) the accuracy of the SSS-Ch compared 50 51 21 to the PHQ-15 for assessing severity. 52 53 54 22 Secondary objective 55 56 57 58 59 60
6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 27 BMJ Open
1 2 3 1 The secondary objective is to explore the potential utility of the SSS-Ch in monitoring BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 treatment effect. We intend to observe the trends in how the score of the SSS-Ch and other 7 8 3 questionnaires after treatment changes over time. 9 10 11 4 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 27
1 2 3 1 METHODS BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Study overview 7 8 9 3 This study will use a prospective diagnostic design and will be conducted at a tertiary general 10 11 4 hospital in Shanghai, China. The study protocol was approved by the ethics committees of 12 13 5 Renji Hospital, and written informed consent will be obtained from all study participants. The 14 15 16 6 clinical trial registration can be found at https://register.clinicaltrials.gov/, and the registration 17 18 7 number is NCT03513185.For peer review only 19 20 21 8 Particular attention will be paid to the appropriate storage of this study. Patient 22 23 9 confidentiality will be maintained, and no identifying features of the patients will be 24 25 10 published. The protocol development will adhere to the EMA guidelines for diagnosis study14. 26 27 28 11 Description of the SSS-Ch and Assessment of Severity 29 30 31 12 The SSS-Ch is a somatic symptom scale (Figure 1) derived from the DSM-5. It queries 32 33 13 approximately 10 somatic clusters that account for 50% of the physical complaints (1 item 34 35 14 per body system, items 1, 5, 9, 10, 12, 13, 16, and 18-20). Anxiety and depression items 36 37 http://bmjopen.bmj.com/ 38 15 compose another 50% (anxiety, 20% (4/20), items 6, 14, 15, and 17; depression, 20% (4/20), 39 40 16 items 3, 4, 7, and 11; and anxiety and depression, 10%, items 2 and 8). Subjects answer the 41 42 17 following question: “Since you have felt unwell, how often have you been bothered in the 43 44 18 previous 6 months by any of the following problems?” For scoring, the subjects rate the 45 on September 25, 2021 by guest. Protected copyright. 46 47 19 frequency of each symptom as 1 (“does not exist”), 2 (“the problem occurred occasionally for 48 49 20 a couple of days per month and/or is endurable”), 3 (“the problem occurred almost half of the 50 51 21 days per month and/or I hope it will ease up”) or 4 (“the problem occurred almost every day 52 53 54 22 and/or is unendurable”). Thus, in determining the SSS-Ch score, each question has a score 55 56 23 ranging from 1 to 4, corresponding to the frequency of the problem occurrence, and the total 57 58 24 score ranges from 20 to 80. The severity categories are assessed according to the sum of the 59 60
8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 27 BMJ Open
1 2 3 1 scores. The SSS-Ch scores range from 20 to 29, 30 to 39, 40 to 59, and ≥60 and represent BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 normal, mild, moderate, and severe SSD, respectively. The selection of these cut-off values 7 8 3 takes into account the results of our previous study15 (a cut-off score of 30 was obtained from 9 10 4 the receiver operating curve (ROC), reaching a sensitivity of 0.97 and a specificity of 0.96) 11 12 5 and clinical experience. 13 14 15 6 Study Design 16 17 18 7 The study is composedFor of 2peer stages (Figure review 2) corresponding only to the primary and secondary 19 20 8 research objectives. The first stage is a prospective diagnostic study to test the diagnostic 21 22 23 9 performance of the SSS-Ch questionnaire. The second stage is an exploratory follow-up stage 24 25 10 that uses the SSS-Ch questionnaire as a tool to monitor treatment effects. 26 27 28 11 Briefly, consecutive outpatients with physical discomfort presenting to internal medicine 29 30 12 departments in a tertiary hospital in China will first undergo the corresponding examination. 31 32 13 Patients with no organic disease that can account for their discomfort will be considered to 33 34 14 have a probability of somatic disorder. Those patients will then be transferred to a specialist 35 36 37 15 clinic for the treatment of suspected SSD. They will successively fill out the SSS-Ch http://bmjopen.bmj.com/ 38 39 16 questionnaire (and other self-reported instruments for the sake of validity estimation), and 40 41 17 non-clinical research assistants will collect the questionnaires and determine the scores. A 42 43 44 18 physician or a psychologist who is blind to the results of the SSS-Ch will separately interview 45 on September 25, 2021 by guest. Protected copyright. 46 19 the patient to diagnose SSD according to the corresponding DSM-5 criteria. Prescriptions 47 48 20 will be given if the patient is diagnosed with SSD. Two-, 6-, and 10-week follow-ups will be 49 50 51 21 scheduled to repeat the questionnaires for patients receiving medications. Since health-related 52 53 22 quality of life is often impaired in patients with SSD, the 20-item Short Form Health 54 55 23 Survey (SF-20) will be administered as an indicator of therapeutic effects during follow-up. 56 57 58 24 Participants and Procedure 59 60
9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 27
1 2 3 1 Inclusion criteria BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 (1) Patients aged 18-80 years old; (2) patients who have no previous diagnosis of somatic 7 8 3 disease; (3) patients without systemic disease that can account for their physical discomfort; 9 10 11 4 and (4) patients enrolled as outpatients after they agree to complete the questionnaires and 12 13 5 undergo assessment by a physician will meet the inclusion criteria. 14 15 16 6 Exclusion criteria 17 18 7 (1) Patients who haveFor lost theirpeer self-assessment review ability oronly refuse to participate; (2) patients 19 20 21 8 who have been previously confirmed to have serious mental disorders, mental retardation or 22 23 9 dementia; (3) patients who are taking anti-anxiety agents or anti-depression agents; and (4) 24 25 10 patients who are deemed unable to complete face-to-face follow-up after at least 1 month 26 27 28 11 (such as those who live abroad) will be excluded from the study. 29 30 12 Reference standard 31 32 33 13 As in Axelsson et al6, judgement by a physician is set as the reference standard to test 34 35 14 consistency. The physician team is composed of both general hospital “specified physicians” 36 37 http://bmjopen.bmj.com/ 38 15 (that is, physicians qualified as national psychological counsellors) and psychologists. The 39 40 16 status of the subject will be assessed by the physician or psychologist using the DSM-5 SSD 41 42 17 criteria (SSD, 300.82 (F45.1) and unspecified somatic symptom and related disorder, 300.82 43 44 18 (F45.9)) (Supplementary Figure 1), anxiety disorder criteria and depression disorder criteria. 45 on September 25, 2021 by guest. Protected copyright. 46 47 19 When there is diagnostic uncertainty, the senior physician will be consulted with. 48 49 20 Assessing capacity and obtaining informed consent 50 51 52 21 Informed consent will be sought by a trained researcher who will provide all necessary 53 54 22 55 information about this study to the potential participants. It will be made clear to participants 56 57 23 that they are under no obligation to take part, their usual care will not be affected by their 58 59 24 decision, and they can withdraw consent without giving a reason. Participants will be given a 60
10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 27 BMJ Open
1 2 3 1 sheet with contact details for the research team and instructions on what to do if they wish to BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 withdraw or require further information. 7 8 3 Blinding 9 10 11 4 After a patient with suspected SSD is transferred to the specialist clinic, the patient will first 12 13 5 complete the questionnaires in a separate room, and the research assistant will help the 14 15 16 6 patient understand the questions. We will also ensure that the patients are comfortable. Then, 17 18 7 an initial consultationFor will bepeer blindly conducted review by a physician only who has been qualified as a 19 20 8 national psychological counsellor. An independent diagnosis and severity category will be 21 22 23 9 assigned by the physician using the DSM-5 criteria. The duration of the self-reported scale 24 25 10 and the physician assessment will be separately recorded. 26 27 28 11 Medication 29 30 12 The patients will be informed of the results immediately after the physician consultation and 31 32 33 13 the questionnaire completion. The patients will communicate with the doctor throughout the 34 35 14 diagnosis and treatment. Since patients in China usually refuse to accept psychotherapy, 36 37 15 medications will be prescribed according to the physician’s evaluation. Anti-anxiety http://bmjopen.bmj.com/ 38 39 16 treatment or anti-depression treatment will be selectively administered according to the 40 41 42 17 severity of the somatic symptom burden. Generally, members of the thioxanthene class, such 43 44 18 as Deanxit, are used for mild symptoms; selective serotonin reuptake inhibitors (SSRIs) are 45 on September 25, 2021 by guest. Protected copyright. 46 19 applied for moderate symptoms; and serotonin-norepinephrine reuptake inhibitors (SNRIs) 47 48 49 20 are applied for severe symptoms, with the serotonin antagonist and reuptake inhibitor (SARI) 50 51 21 class prescribed if sleeping problems exist. 52 53 54 22 Follow-up 55 56 57 58 59 60
11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 27
1 2 3 1 A face-to-face interview will be scheduled at 2, 6, and 10 weeks to follow up using the SSS- BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Ch, PHQ-15, PHQ-9 and GAD-7 questionnaires for patients taking medication. An SF-20 7 8 3 survey will be conducted to evaluate quality of life. 9 10 11 4 Outcome measures 12 13 5 Reliability and validity 14 15 16 6 Reliability will be measured by Cronbach’s alpha. A randomized sample of approximately 17 18 7 100 participants willFor be askedpeer to complete review the questionnaires only 1 week after the initial 19 20 21 8 completion to analyse the test-retest reliability. 22 23 9 The criterion validity will be calculated by the correlations of the diagnostic results and the 24 25 26 10 severity assessments of somatic symptoms between the SSS-Ch and the reference standard. 27 28 11 The SSS-Ch consists of 10 questions for somatic symptoms, 4 for depression, 4 for 29 30 31 12 anxiety, and 2 for depression and anxiety. The construct validity will be tested by 32 33 13 confirmatory factor analysis, comparing the corresponding factors with the PHQ-15, Patient 34 35 14 Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7). 36 37 http://bmjopen.bmj.com/ 38 15 Diagnostic performance 39 40 41 16 The diagnostic accuracy of a questionnaire for SSD identification is measured by the area 42 43 17 under the curve (AUC) of an ROC, the sensitivity/specificity under a prespecified cut-off 44 45 18 value, and the positive/negative predictive values in the study population, referring to the on September 25, 2021 by guest. Protected copyright. 46 47 48 19 physician diagnosis as the reference standard. The accuracy of the severity assessment of a 49 50 20 questionnaire is measured by the Spearman correlation between the questionnaire score and 51 52 21 the physician’s severity assessment. 53 54 55 22 Other Clinical utilities 56 57 58 23 Convenience in clinical practice is measured by the average time taken to complete each 59 60 24 questionnaire or receive a diagnosis from a physician.
12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 27 BMJ Open
1 2 3 1 Clinical utility in monitoring treatment efficacy in patients is measured by correlation with BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 the SF-20 during follow-up visits. 7 8 3 Sample size calculation 9 10 11 4 The sample size calculation considers the comparison of diagnostic accuracy for both SSD 12 13 5 identification and severity assessment, whichever is larger. In the pilot study, the prevalence 14 15 16 6 of SSD was 76.9% in the study population who were referred to the special clinics, the AUC 17 18 7 of the ROC for PHQ-15For was peer 0.88, and Spearman’sreview correlation only of the PHQ-15 score with the 19 20 8 physician's diagnosis was 0.77 (95% CI: 0.43, 0.92). The correlation of the SSS-Ch and 21 22 23 9 PHQ-15 scores was set to 0.6. With a non-inferiority margin of 0.05, α=0.025, and β=0.8, the 24 25 10 sample size for SSD diagnosis was 852. With a non-inferiority margin of 0.1, α=0.025, and 26 27 11 β=0.8, the sample size for severity assessment was 579. Therefore, as the overall sample size 28 29 12 of this study was N=852 with SSD-positive N+=655 and SSD-negative N-=197, both the 30 31 32 13 positive and negative sample size requirements were met. 33 34 14 Statistical analysis 35 36 37 15 We will report our results according to STARD. We will compute the median (P25, P75) http://bmjopen.bmj.com/ 38 39 16 scores for each questionnaire and the number and percentage of patients (%) in each 40 41 42 17 diagnostic category as descriptive statistics. 43 44 18 Reliability will be measured using Cronbach’s α. The criterion validity will be measured 45 on September 25, 2021 by guest. Protected copyright. 46 47 19 by the kappa coefficient of diagnosis and the Kendall tau-b of severity assessment. Construct 48 49 20 validity will be tested using confirmatory factor analyses. 50 51 52 21 The primary analysis of the diagnostic performance will consist of two comparisons using 53 54 22 Bonferroni correction: (1) the non-inferior comparison of the SSS-Ch with the PHQ-15 in 55 56 23 SSD diagnostic accuracy as measured by the AUC of the ROC with =0.05, =0.025 in the 57 58 59 24 whole study population using Delong’s method16 and (2) the non-inferior comparison of the 60
13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 27
1 2 3 1 SSS-Ch with the PHQ-15 in SSD severity assessment measured by Spearman’s correlation BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 with =0.1, =0.025 in the population with a confirmed SSD diagnosis using Fisher’s Z test. 7 8 3 Both comparisons refer to the physician’s diagnosis as the reference standard. If either non- 9 10 4 inferiority criterion is met, the corresponding superiority will be tested. 11 12 13 5 As a secondary analysis, the sensitivity, specificity, and positive and negative predictive 14 15 6 values will also be reported. Prespecified cut-off values will be validated. In addition, we will 16 17 18 7 compare the time neededFor to completepeer each review questionnaire and only be diagnosed by a physician. 19 20 8 In the follow-up data, questionnaire scores by time will be demonstrated in a line chart with 21 22 23 9 error bars. 24 25 10 Missing values will be imputed with multiple imputation17. Subgroup analysis according to 26 27 28 11 gender and age will also be conducted. All statistical analyses will be performed with R 29 30 12 (version 3.5.1) 31 32 33 13 Patient and public involvement statement 34 35 14 Patients were involved at the design stage of the trial, including clarifying the 36 37 http://bmjopen.bmj.com/ 38 15 understandability of the SSS-Ch questionnaire and discussing the length of the consultation 39 40 16 time, the manner of notification of the disease condition, the follow-up method, and the 41 42 17 dissemination of the results. Before the formal recruitment started, we received feedback 43 44 45 18 from patients who had SSD during a pretest of the case report form (CRF) and used it to on September 25, 2021 by guest. Protected copyright. 46 47 19 improve the final design of the CRF. We carefully assessed the burden of the trial 48 49 20 interventions on patients. We intend to disseminate the main results to the trial participants 50 51 52 21 via email. The study outcomes will be disseminated in conference reports and academic 53 54 22 publications. 55 56 57 23 Current status 58 59 60
14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 27 BMJ Open
1 2 3 1 The first study participant was enrolled in November 2017. In November 2018, patient BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 recruitment was not completed. 7 8 3 9 10 11 4 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 27
1 2 3 1 DISCUSSION BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 In this study protocol, we describe a diagnostic study design that evaluates the efficacy of a 7 8 3 newly developed somatic symptom scale adapted to China for patients with suspected 9 10 11 4 somatic diseases that might be applied as a first-line instrument for screening and monitoring 12 13 5 treatment efficacy in individual outpatient consultations. We expect that a physician will 14 15 6 benefit from the SSS-Ch on a clinically significant level through improved self-confidence 16 17 7 and timeliness and that the participants will benefit through improving their awareness of the 18 For peer review only 19 20 8 disease and ability to self-monitor their symptoms. Moreover, we will examine the 21 22 9 characteristics of the SSS-Ch compared with other somatic symptom questionnaires. 23 24 25 10 Our SSS-Ch is designed as a “one-stop shop” tool that combines somatic items with 26 27 11 mental disorder items. This design is consistent with the suggestion in the DSM-5 that 28 29 12 somatic symptoms are likely accompanied by depression and anxiety1. Somatic symptoms 30 31 32 13 may interact with mental items, and mental symptoms may be triggered differently than 33 34 14 conventional mental diseases in this group. Clinically, it is not easy to clearly separate body 35 36 15 from mental status, and the significance of each item is unknown. We caution that 50% of 37 http://bmjopen.bmj.com/ 38 39 16 mental items have the possibility of increasing the incidence of SSD, and a subgroup score 40 41 17 with somatic symptom items alone is used for this appraisal. 42 43 44 18 The study has several strengths. First, we will introduce a tool to facilitate daily clinical 45 on September 25, 2021 by guest. Protected copyright. 46 19 work. The tool provides clinicians with an easy-to-use questionnaire that can be completed 47 48 20 quickly to improve physicians’ comfort level in screening suspected SSD patients and to refer 49 50 51 21 them to specific doctors. Second, our previous study has shown the reliability and factorial 52 53 22 validity of the SSS-Ch by utilizing an early version of it13. The current study further modifies 54 55 23 the SSS-Ch based on the DSM-5 and, for the first time, evaluates its clinical utility. Third, 56 57 24 patients will benefit by improving their awareness of the disease and their ability to self- 58 59 60 25 monitor their symptoms.
16 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 27 BMJ Open
1 2 3 1 This trial has some limitations. First, SSD can be accompanied by diagnosed medical BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 disorders. The current study, however, represents the efficacy of the SSS-Ch only in patients 7 8 3 without organic diseases. Therefore, the further application of the SSS-Ch to patients with 9 10 4 specific diseases should be separately investigated. Moreover, the epidemiology of health 11 12 5 care facilities is different from that of general hospitals; therefore, the diagnostic accuracy in 13 14 15 6 a health care sample needs additional investigation. Second, there is no gold standard for SSD 16 17 7 diagnosis. Similar to Axelsson et al., our study uses an appraisal by an “experienced” 18 For peer review only 19 8 physician team as the reference standard. In this way, we measure only the consistency 20 21 22 9 between the physician assessment and questionnaire score. Third, the study was designed as a 23 24 10 mid-term investigation with four measurement time points, and thus missing data must be 25 26 11 considered. Referring to the fact that only 16% of patients in the primary care evaluation of 27 28 18 29 12 mental disorders (PRIME-MD) study were involved in the follow-up , we estimate that a 30 31 13 high rate of missing data will also occur in our patients. Fortunately, each subject in our study 32 33 14 will undergo the same set of questionnaires for the entire scale, and thus the missing samples 34 35 15 lost to follow-up will not differ among the groups; therefore, they will not produce significant 36 37 http://bmjopen.bmj.com/ 38 16 bias and will not affect our assessment. 39 40 17 41 This study will help to clarify whether the developed SSS-Ch score is an effective tool for 42 43 18 rapid screening and assessment of severity in patients with suspected SSD in a general 44 45 19 hospital clinic and for convenient follow-up. If the SSS-Ch is found to be effective, it can be on September 25, 2021 by guest. Protected copyright. 46 47 20 implemented as a first-line screening and follow-up option. Additionally, we expect that the 48 49 50 21 SSS-Ch could provide personalized information to consulting physicians in a timely manner. 51 52 22 The study results will contribute to better outpatient care for patients with SSD. 53 54 55 23 56 57 24 58 59 60
17 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 27
1 2 3 Acknowledgements: We thank all the patients who participated and advised us throughout BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 the study design and implementation for their contributions. 7 8 Conflict of interests: The authors declare that they have no competing interests. 9 10 Ethical approval: Ethical approval was provided by the Renji Hospital Human Research 11 12 Ethics Committee, approval number 2015016. 13 14 15 Consent for publication: All participants to date have provided written informed consent. 16 17 Authors' contributions: JLM: substantial contributions to the conception, design and 18 For peer review only 19 interpretation of data, drafting and critical revisions for important intellectual content. WTZ: 20 21 22 analysis, statistics and interpretation of data, drafting the manuscript. XS: design and 23 24 implementation of study, acquisition of data, analysis and interpretation of data, drafting the 25 26 manuscript. CG: analysis, statistics and interpretation of data. BXC: acquisition of data, 27 28 29 analysis and interpretation of data, drafting the manuscript. ZHF: acquisition of data, analysis 30 31 and interpretation of data, drafting the manuscript. MJ: substantial contributions to the 32 33 conception, design and interpretation of data, critical revisions for important intellectual 34 35 content. JP: substantial contributions to the conception, design and interpretation of data. 36 37 http://bmjopen.bmj.com/ 38 Funding: This work was supported by the National Science Fund for Distinguished Young 39 40 Scholars (81625002) for patient enrolment; National Natural Science Foundation of China 41 42 (81470391, 81470389) for physician consultation; Shanghai Outstanding Academic Leaders 43 44 45 Programme (18XD1402400) for data analysis; Shanghai Municipal Education Commission – on September 25, 2021 by guest. Protected copyright. 46 47 Gaofeng Clinical Medicine Grant Support (20152209 and 20172014) for follow-up 48 49 consultation; Shanghai Science and Technology Committee (15411963600) for seminars; and 50 51 52 Shanghai ShenKang Hospital Development Centre (16CR3020A and 16CR3034A) for data 53 54 collection. 55 56 Registration name: The validation and utility of the somatic symptom scale China (SSS-Ch) 57 58 for assessing somatic symptom disorder in general hospital outpatients. 59 60
18 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 27 BMJ Open
1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 1. Barsky AJ, Orav EJ, Bates DW. Somatization increases medical utilization and costs 7 8 independent of psychiatric and medical comorbidity. Archives of general psychiatry 9 10 11 2005;62(8):903-10. doi: 10.1001/archpsyc.62.8.903 12 13 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 14 15 Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Association Publishing 16 17 2013. 18 For peer review only 19 20 3. Barsky AJ. Assessing somatic symptoms in clinical practice. JAMA Intern Med 21 22 2014;174(3):407-8. doi: 10.1001/jamainternmed.2013.12177 23 24 4. Jr SG. The course of somatization and its effects on utilization of health care resources. 25 26 27 Psychosomatics 1994;35(3):263. 28 29 5. Hahn SR, Kroenke K, Spitzer RL, et al. The difficult patient: prevalence, psychopathology, 30 31 and functional impairment. Journal of General Internal Medicine 1996;11(1):1. 32 33 34 6. Axelsson E, Andersson E, Ljotsson B, et al. The health preoccupation diagnostic interview: 35 36 inter-rater reliability of a structured interview for diagnostic assessment of DSM-5 37 http://bmjopen.bmj.com/ 38 somatic symptom disorder and illness anxiety disorder. Cogn Behav Ther 39 40 41 2016;45(4):259-69. doi: 10.1080/16506073.2016.1161663 42 43 7. Laferton JAC, Stenzel NM, Rief W, et al. Screening for DSM-5 Somatic Symptom 44 45 Disorder: Diagnostic Accuracy of Self-Report Measures Within a Population Sample. on September 25, 2021 by guest. Protected copyright. 46 47 Psychosom Med 2017;79(9):974-81. doi: 10.1097/PSY.0000000000000530 48 49 50 8. Gierk B, Kohlmann S, Kroenke K, et al. The somatic symptom scale-8 (SSS-8): a brief 51 52 measure of somatic symptom burden. JAMA Intern Med 2014;174(3):399-407. doi: 53 54 10.1001/jamainternmed.2013.12179 55 56 57 9. Gierk B, Kohlmann S, Toussaint A, et al. Assessing somatic symptom burden: a 58 59 psychometric comparison of the patient health questionnaire-15 (PHQ-15) and the 60
19 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 27
1 2 3 somatic symptom scale-8 (SSS-8). J Psychosom Res 2015;78(4):352-5. doi: BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 10.1016/j.jpsychores.2014.11.006 7 8 10. Toussaint A, Murray AM, Voigt K, et al. Development and Validation of the Somatic 9 10 Symptom Disorder-B Criteria Scale (SSD-12). Psychosom Med 2016;78(1):5-12. doi: 11 12 10.1097/PSY.0000000000000240 13 14 15 11. Toussaint A, Lowe B, Brahler E, et al. The Somatic Symptom Disorder - B Criteria Scale 16 17 (SSD-12): Factorial structure, validity and population-based norms. J Psychosom Res 18 For peer review only 19 2017;97:9-17. doi: 10.1016/j.jpsychores.2017.03.017 20 21 22 12. Tu CY, Liao SC, Liu CY, et al. Application of the Chinese Version of the Whiteley 23 24 Index-7 for Detecting DSM-5 Somatic Symptom and Related Disorders. 25 26 Psychosomatics 2016;57(3):283-91. doi: 10.1016/j.psym.2015.12.010 27 28 29 13. Qi Z, Jialiang M, Chunbo L, et al. Developing of somatic self-rating scale and its 30 31 reliability and validity. Chinese Journal of Behavioral Medicine and Brain Science 32 33 2010;19(9):847-9. 34 35 14. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use: 36 37 http://bmjopen.bmj.com/ 38 Guideline on clinical evaluation of diagnostic agents. 39 40 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/ 41 42 09/WC500003584.pdf. 43 44 45 15. Organization WH. The ICD-10 Classification of Mental and Behavioural Disorders: on September 25, 2021 by guest. Protected copyright. 46 47 Clinical Description and Diagnostic Guidelines: WHO 1993. 48 49 16. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more 50 51 52 correlated receiver operating characteristic curves: a nonparametric approach. 53 54 Biometrics 1988;44(3):837-45. 55 56 17. Buuren S, Groothuis-Oudshoorn K. mice: Multivariate imputation by chained equations 57 58 in R. Journal of statistical software, 2010; 1-68. 59 60
20 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 27 BMJ Open
1 2 3 18. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental 7 8 Disorders. Patient Health Questionnaire. Jama 1999;282(18):1737-44. 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 27
1 2 3 Figure Legends BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 Figure 1 The Somatic Symptom Scale-China (SSS-Ch). 7 8 9 Figure 2 Study flow. SSS-Ch, Somatic Symptom Scale-China; PHQ-15: Patient Health 10 11 Questionnaire-15; PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety 12 13 Disorder Scale-7; SF-20: 20-Item Short Form Health Survey; SSD: Somatic Symptom 14 15 16 Disorder. 17 18 For peer review only 19 Supplementary Figure 1 Criteria of somatic symptom disorder, unspecified somatic 20 21 symptoms and related disorders from the DSM-5 (adapted from American Psychiatric 22 23 24 Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)). 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
22 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 27 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 345x199mm (300 x 300 DPI) 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 168x262mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 27
1 2 3 TITLE OR BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 PageABSTRACT 1, line 1-2 1 Identification as a study of diagnostic accuracy using at least one measure 5 of accuracy (such as sensitivity, specificity, predictive values, or AUC) 6 ABSTRACT 7 Page 2, line 2-18 for 2 Structured summary of study design, methods, results, and conclusions 8 protocol article 9 (for specific guidance, see STARD for Abstracts) 10 INTRODUCTION 11 Page 4-5, line 2-21 3 Scientific and clinical background, including the intended use and clinical 12 role of the index test 13 Page 5, line 22-page 6, 4 Study objectives and hypotheses 14 line3; Page 6,line 17-page 15 7, line 3 16 METHODS 17 Study design 5 Whether data collection was planned before the index test and reference 18 Page 8, line 3; Page For14,line peerstandard reviewwere performed (prospectiveonly study) or after (retrospective study) 19 13-22 20 Participants 6 Eligibility criteria 21 Page 10,line 1-11 22 Page 9,line 12-16 7 On what basis potentially eligible participants were identified 23 (such as symptoms, results from previous tests, inclusion in registry) 24 Page 9, line 12-21 8 Where and when potentially eligible participants were identified (setting, 25 location and dates) 26 Page 9, line 12 9 Whether participants formed a consecutive, random or convenience series 27 Test methods 10a Index test, in sufficient detail to allow replication 28 Page 8,line 12-page 9, 29 line 6; Figure 1 30 Page 10,line 12-19;Suppl 31 10b Reference standard, in sufficient detail to allow replication Fig1 32 33 Page 4,line 23-page 5, line 11 Rationale for choosing the reference standard (if alternatives exist) 34 5 35 Page 8,line 19-page 9,line 12a Definition of and rationale for test positivity cut-offs 36 6 or result categories of the index test, distinguishing 37 Suppl Fig1 12b pre-specifiedDefinition of andfrom rationale exploratory for test positivity cut-offs or result categories http://bmjopen.bmj.com/ 38 of the reference standard, distinguishing pre-specified from exploratory 39 Page 9, line 18-21 13a Whether clinical information and reference standard results were 40 available 41 Page 9, line 16-18; Page 13b Whetherto the performers/readers clinical information of the and index index test test results were available 42 12, line 1-3 43 to the assessors of the reference standard 44 Analysis 14 Methods for estimating or comparing measures of diagnostic accuracy 45 Page12，line 15-21 ， 15 How indeterminate index test or reference standard results were handled on September 25, 2021 by guest. Protected copyright. 46 Page10 line 19 47 Page 14,line 10-12 16 How missing data on the index test and reference standard were handled 48 Page12，line 15-21 17 Any analyses of variability in diagnostic accuracy, distinguishing pre- 49 specified from exploratory 50 Page 13, line 3-13 18 Intended sample size and how it was determined 51 RESULTS 52 Participants 19 Flow of participants, using a diagram 53 54 NA 20 Baseline demographic and clinical characteristics of participants 55 NA 21a Distribution of severity of disease in those with the target condition 56 NA 21b Distribution of alternative diagnoses in those without the target condition 57 NA 22 Time interval and any clinical interventions between index test and 58 reference standard 59 Test results 23 Cross tabulation of the index test results (or their distribution) 60 by the results of the reference standard
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 27 BMJ Open
1 2 3 NA 24 Estimates of diagnostic accuracy and their precision (such as 95% BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 confidence intervals) 6 NA 25 Any adverse events from performing the index test or the reference 7 standard 8 DISCUSSION 9 Page 17,line 1-16 26 Study limitations, including sources of potential bias, statistical 10 uncertainty, and generalisability 11 Page 16,line 2-9;line 18- 27 Implications for practice, including the intended use and clinical role of 12 25; Page 17,line 17-22 the index test 13 OTHER 14 PageINFORMATION 2,line 24;Page 28 Registration number and name of registry 15 18,line 23-24； 16 NA 29 Where the full study protocol can be accessed 17 Page 18,line 15-22 30 Sources of funding and other support; role of funders 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
Research Protocol for a Diagnostic Study: Identifying and Measuring the Severity of Somatic Symptom Disorder Using the Self-reported Somatic Symptom Scale-China (SSS-CN) ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024290.R2
Article Type: Protocol
Date Submitted by the 09-Mar-2019 Author:
Complete List of Authors: Jiang, Meng; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Zhang, Weituo; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Su, Xuan; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Gao, Chuang; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Chen, Bingxu; School of Medicine, Shanghai Jiao Tong University Feng, Zehao; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Mao, Jialiang; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology http://bmjopen.bmj.com/ Pu, Jun; Renji Hospital, School of Medicine, Shanghai Jiaotong University
Primary Subject Mental health Heading:
Secondary Subject Heading: Research methods
Somatic Symptom Scale-China, somatic symptom disorder, mental Keywords: disorders management on September 25, 2021 by guest. Protected copyright.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 24 BMJ Open
1 2 3 1 Research Protocol for a Diagnostic Study: Identifying and Measuring the Severity of BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 Somatic Symptom Disorder Using the Self-reported Somatic Symptom Scale-China (SSS- 7 8 3 CN) 9 10 4 11 12 5 Meng Jianga1, MD, PhD, Weituo Zhanga2, PhD, Xuan Su1, MD, Chuang Gao2, MPH, Bingxu 13 14 3 1 *1 *1 15 6 Chen , MD, Zehao Feng , MD, Jialiang Mao , MD, PhD, Jun Pu , MD, PhD 16 17 7 18 For peer review only 19 8 1 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 20 21 9 Shanghai, China 200127; 2 Clinical Research Center, School of Medicine, Shanghai Jiao Tong 22 23 3 24 10 University, Shanghai, China 200025; School of Medicine, Shanghai Jiao Tong University, 25 26 11 Shanghai, China 200025 27 28 12 29 30 13 a Co-first author: Meng Jiang and Weituo Zhang contributed equally to the paper. 31 32 33 14 * Names and addresses correspondence: Jialiang Mao, MD, PhD; Jun Pu, MD, PhD, FACC, 34 35 15 FESC; Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong 36 37 16 University, Shanghai, China; 160 Pujian Road, Shanghai, China, 200127. Tel: 086-21-68383447, http://bmjopen.bmj.com/ 38 39 17 Fax: 086-21-68383447; Email: [email protected]; [email protected]. 40 41 42 18 43 44 19 Word count: 4975 45 on September 25, 2021 by guest. Protected copyright. 46 20 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 24
1 2 3 1 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Aim The recognition rate of somatic symptom disorder (SSD) in general hospitals is 7 8 3 unsatisfactory. Self-report questionnaires that combine both somatic symptoms and psychological 9 10 4 characteristics are useful in screening for SSD. The Somatic Symptom Scale-China (SSS-CN) 11 12 13 5 questionnaire was developed due to urgent clinical demand. The aim of this research is to validate 14 15 6 the self-reported SSS-CN as a timely and practical instrument to identify SSD and to assess the 16 17 7 severity of this disorder. 18 For peer review only 19 20 8 Methods and Analysis At least 852 patients without organic disease but presenting with 21 22 9 physical discomfort will be recruited at a general hospital. Each patient will undergo a DSM-5- 23 24 10 guided physician diagnosis, including disease identification and severity assessment, as a 25 26 27 11 reference standard. This research will utilize the SSS-CN to evaluate its diagnostic performance 28 29 12 in SSD compared to that of the Patient Health Questionnaire-15 (PHQ-15) and other SSD- 30 31 13 related questionnaires. Statistical tests for the area under the curve (AUC) and volume under the 32 33 14 surface (VUS) of the receiver operating curve (ROC) will be used to compare the accuracy of the 34 35 36 15 SSD identification and severity assessment, respectively. In addition to this standard diagnostic 37 http://bmjopen.bmj.com/ 38 16 study, we will conduct follow-up investigations to explore the characteristics of the SSS-CN in 39 40 17 monitoring treatment effects. 41 42 18 43 44 45 19 on September 25, 2021 by guest. Protected copyright. 46 47 20 Ethics and Dissemination Ethical approval was provided by the Renji Hospital Human 48 49 21 50 Research Ethics Committee, approval number 2015016. The findings of this study will be 51 52 22 disseminated via peer-reviewed journals and presented at international conferences. 53 54 23 Trial registration number: NCT03513185 55 56 57 24 58 59 60
2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 24 BMJ Open
1 2 3 1 Strengths and Limitations of this Study BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 1. First, we introduce a tool to benefit patients and to facilitate daily clinical work. The 7 8 3 primary goal is to screen suspected somatic symptom disorder (SSD) patients via accurate 9 10 4 and brief diagnostic tools. Patients will benefit by improving their awareness of the disease 11 12 13 5 and their ability to self-monitor their symptoms. Additionally, the tool provides clinicians 14 15 6 with an easy-to-use questionnaire that can be completed quickly and combines both 16 17 7 somatic and psychological features. 18 For peer review only 19 20 8 2. Second, our previous study has shown the reliability and factorial validity of the Somatic 21 22 9 Symptom Scale-China (SSS-CN) by utilizing an early version of the scale. The current study 23 24 10 further modifies the SSS-CN based on the DSM-5 and, for the first time, is applied to 25 26 27 11 evaluate its clinical utility. 28 29 12 3. A potential limitation of this study is that it represents the efficacy of the SSS-CN only in 30 31 13 32 patients without organic disease. Further research on the application of SSS-CN in patients 33 34 14 with both SSD and diagnosed medical disorders is required. 35 36 15 4. Because only patients without a positive physical examination will be referred to the special 37 http://bmjopen.bmj.com/ 38 39 16 clinic, a referral bias exists due to the nature of our clinic. Moreover, the epidemiology of 40 41 17 health care facilities is different from that of general hospitals; therefore, the diagnostic 42 43 18 accuracy in a health care sample needs additional investigation. 44 45 on September 25, 2021 by guest. Protected copyright. 46 19 5. The potential of monitoring the treatment effect will be affected by loss to follow-up bias 47 48 20 due to the unpredictable pattern of loss to follow-up. 49 50 51 21 52 53 22 Keywords 54 55 56 23 Somatic Symptom Scale-China; somatic symptom disorder; mental disorders management 57 58 59 60
3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 24
1 2 3 1 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 One of the common medical conditions observed in general hospitals is somatic symptom 7 8 3 disorder (SSD) and related disorders1 2. SSD refers to symptoms that are often difficult to explain 9 10 4 after adequate evaluation3; even when a significant medical disease is present, the patients’ 11 12 2 13 5 symptoms may nonetheless be unrelated to their disease . The diagnosis of SSD emphasizes the 14 15 6 existence of symptoms and signs (one or multiple somatic symptoms plus abnormal thoughts, 16 17 7 feelings, and behaviours in response to these symptoms)2. The disorder has an estimated current 18 For peer review only 19 8 prevalence in the general population of 5-7%2. The prevalence is estimated to be higher in 20 21 4 22 9 China . Individuals with somatic symptoms are commonly encountered in general hospitals and 23 24 10 primary care as well as in psychiatric and other mental health settings2. The recognition rate of 25 26 11 SSD is unsatisfactory due to the diagnostic complexity, and some physicians may not feel 27 28 12 sufficiently trained to evaluate patients with suspected SSD; thus, SSD could be underdiagnosed 29 30 31 13 in routine care. Therefore, patients may sustain somatic symptoms without appropriate treatment 32 33 14 due to the lack of awareness of SSD. Patients with somatization had approximately twice as 34 35 15 much cost as patients without somatization on medical care utilization and annual medical care. 36 37 16 An estimated $256 billion in annual medical care costs is attributable to the incremental effects http://bmjopen.bmj.com/ 38 39 1 40 17 of somatization alone . Whereas depression and anxiety disorders are widely researched, SSD has 41 42 18 been far less studied. Follow-up or treatment studies of this disorder are even scarcer. Hence, it 43 44 19 is highly important that physicians are prepared to identify SSD, assess the symptom severity and 45 on September 25, 2021 by guest. Protected copyright. 46 20 treat it in a timely manner; failure to do so can result in high degrees of morbidity, lost 47 48 5 6 49 21 productivity, and overutilization of medical resources . 50 51 22 The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) aims to 52 53 23 identify SSD patients and assessing the severity of the disorder2. It agreed that the SSD 54 55 24 companioned anxiety and depressive disorder (in approximately 57.7% of SSD patients)1 adds 56 57 58 25 severity and complexity to the somatic components. It emphasizes that it is important to evaluate 59 60 26 patients in terms of their psychological situation, behaviour and physical condition altogether
4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 24 BMJ Open
1 2 3 1 and then treat the patients according to the severity of the disorder. It also emphasizes the BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 evaluation in subjects who have excessive concerns about health issues. Recent studies, including 7 8 3 one by Laferton et al., have also indicated that the combination of self-report measures could 9 10 4 increase diagnostic quality in clinical practice7. The DSM-5, however, is clinically difficult to 11 12 5 follow because it depends on qualified and experienced physicians conducting an interview8, 13 14 6 15 which makes clinicians in the general hospital feel less confident in dealing with such individuals. 16 17 7 On the other hand, individuals in China usually refuse to receive psychological counselling. Thus, 18 For peer review only 19 8 in general medical hospitals, non-psychiatric physicians must face more patients with 20 21 9 psychological symptoms. It is more favourable to have a tool to screen suspected SSD patients 22 23 10 24 via accurate and brief diagnostic questionnaires and to facilitate daily clinical work. A series of 25 26 11 studies has focused on this issue; the Patient Health Questionnaire-15 (PHQ-15) and the 27 28 12 Somatic Symptom Scale-8 are screening tools for SSD9 10; however, these types of self-report 29 30 13 questionnaires do not incorporate psychological features. The Whiteley Index-7 focuses on 31 32 14 11 33 health anxiety , the Scale for the Assessment of Illness Behavior questionnaires focuses on 34 12 35 15 excessive illness behaviour, and the Somatic Symptom Scale-12 assesses psychological features 36 37 16 13
. The latter three questionnaires focus less on physical features. http://bmjopen.bmj.com/ 38 39 40 17 Based on published studies, we aim to develop a self-administered questionnaire to provide a 41 42 18 comprehensive reflection of both somatic and psychological features. The Somatic Symptom 43 44 19 Scale-China (SSS-CN) questionnaire was developed based on the DSM-5. Psychology and 45 on September 25, 2021 by guest. Protected copyright. 46 20 behaviour items are interleaved with somatic symptoms. It incorporates affective, cognitive, and 47 48 49 21 behavioural components. It is designed to be used in general medical facilities and to provide 50 51 22 clinicians with an easy-to-use questionnaire to detect both somatic and psychological features in a 52 53 23 time-saving way. 54 55 56 24 Study Objectives and Research Questions 57 58 25 59 Primary objective 60
5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 24
1 2 3 1 The primary objective of this study is to test two types of diagnostic accuracy with a DSM-5-guided BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 physician diagnosis as the reference standard: (1) the accuracy of the SSS-CN compared to the 7 8 3 PHQ-15 for identifying SSD and (2) the accuracy of the SSS-CN compared to the PHQ-15 for 9 10 4 assessing severity. 11 12 13 5 Secondary objective 14 15 6 The secondary objective is to explore the potential utility of the SSS-CN in monitoring the 16 17 7 18 treatment effect. WeFor intend topeer observe thereview trends in how onlythe score of the SSS-CN and other 19 20 8 questionnaires after treatment changes over time. 21 22 9 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 24 BMJ Open
1 2 3 1 METHODS BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Study Overview 7 8 9 3 This study will use a prospective diagnostic design and will be conducted at a tertiary general 10 11 4 hospital in Shanghai, China. The study protocol was approved by the ethics committees of Renji 12 13 5 Hospital, and written informed consent will be obtained from all study participants. The clinical 14 15 6 trial registration can be found at https://register.clinicaltrials.gov/, and the registration number is 16 17 7 18 NCT03513185. For peer review only 19 20 8 Particular attention will be paid to the appropriate storage of the data. Patient confidentiality will 21 22 9 23 be maintained, and no identifying features of the patients will be published. The protocol 24 14 25 10 development will adhere to the European Medicines Agency guidelines for diagnosis study . 26 27 11 Description of the SSS-CN and Assessment of Severity 28 29 30 12 The SSS-CN is a somatic and psychological symptom scale (Figure 1) derived from the DSM- 31 32 13 5. It is designed to assess the presence and severity of the symptoms. Our previous study validated 33 34 15 35 14 its reliability and validity . The test-retest reliability was 0.9. The correlation coefficient between 36 37 15 each dimension and the total was between 0.76 and 0.88, and the correlation coefficient within http://bmjopen.bmj.com/ 38 39 16 dimensions was 0.56-0.70. 40 41 42 17 The questionnaire is self-administered with an abbreviated 20-item measure. Briefly, in that 43 44 18 study, the SSS-CN was composed of 4 dimensions: physical disorder, anxiety disorder, depression 45 on September 25, 2021 by guest. Protected copyright. 46 19 disorder, and anxiety and depression disorder. The SSS-CN assesses 10 somatic clusters that 47 48 20 49 account for 50% of the physical complaints (1 item per body system, items 1, 5, 9, 10, 12, 13, 16, 50 51 21 and 18-20). Anxiety and depression items account for the remaining 50% (anxiety, 20% (4/20), 52 53 22 items 6, 14, 15, and 17; depression, 20% (4/20), items 3, 4, 7, and 11; and anxiety and depression, 54 55 23 10%, items 2 and 8). Subjects answer the following question: “Since you have felt unwell, how 56 57 24 58 often have you been bothered in the previous 6 months by any of the following problems?” For 59 60 25 scoring, the subjects rate the frequency of each symptom as 1 (“does not exist”), 2 (“the problem
7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 24
1 2 3 1 occurred occasionally for a couple of days per month and/or is endurable”), 3 (“the problem BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 occurred almost half of the days per month and/or I hope it will ease up”) or 4 (“the problem 7 8 3 occurred almost every day and/or is unendurable”). Thus, in determining the SSS-CN score, each 9 10 4 question has a score ranging from 1 to 4, corresponding to the frequency of the problem 11 12 5 occurrence, and the total score ranges from 20 to 80. The severity categories are assessed according 13 14 6 15 to the sum of the scores. The SSS-CN scores range from 20 to 29, 30 to 39, 40 to 59, and ≥60 and 16 17 7 represent normal, mild, moderate, and severe SSD, respectively. The selection of these cut-off 18 For peer review only 19 8 values takes into account the results of our previous study16 (a cut-off score of 30 was obtained 20 21 9 from the receiver operating curve (ROC), reaching a sensitivity of 0.97 and a specificity of 0.96) 22 23 10 24 and clinical experience. 25 26 11 Study Design 27 28 29 12 The study is composed of 2 stages (Figure 2) corresponding to the primary and secondary research 30 31 13 objectives. The first stage is a prospective diagnostic stage to test the diagnostic performance of 32 33 14 the SSS-CN questionnaire. The second stage is an exploratory follow-up stage that uses the SSS- 34 35 36 15 CN questionnaire as a tool to monitor treatment effects. 37 http://bmjopen.bmj.com/ 38 16 Briefly, consecutive outpatients with physical discomfort presenting to internal medicine 39 40 17 41 departments in a tertiary hospital in China will first undergo the corresponding examination to 42 43 18 exclude organic disease. For example, a patient with chest pain would be recommended by a 44 45 19
physician to receive an EKG, echocardiography, a treadmill test or coronary angiography to on September 25, 2021 by guest. Protected copyright. 46 47 20 exclude cardiovascular disease. Patients with no organic disease that can account for their 48 49 21 50 discomfort will be considered to have a probable psychosomatic disorder. These patients will then 51 52 22 be transferred to a specialist clinic for the diagnosis and treatment of suspected SSD (the initial 53 54 23 consultation). They will fill out the SSS-CN questionnaire, we use other self-reported instruments 55 56 24 including PHQ15, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder Scale-7 57 58 25 59 (GAD-7) and SF-20, to verify the structural validity of SSS-CN. Non-clinical research assistants 60
8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 24 BMJ Open
1 2 3 1 will collect the questionnaires and determine the scores. A physician or a psychologist who is blind BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 to the results of the SSS-CN will separately interview the patient to diagnose SSD base on the 7 8 3 standard interview according to the corresponding DSM-5 criterion. Prescriptions will be given if 9 10 4 the patient is diagnosed with SSD. Follow ups will be scheduled at 2, 6, and 10 weeks to repeat the 11 12 5 questionnaires for patients receiving medications (the follow-up consultation). Because health- 13 14 6 15 related quality of life is often impaired in patients with SSD, the 20-item Short Form Health 16 17 7 Survey (SF-20) will be administered as an indicator of therapeutic effects during follow-up. 18 For peer review only 19 8 Participants and Procedure 20 21 22 9 Inclusion criteria 23 24 25 10 (1) Patients aged 18-80 years old; (2) patients who have no previous diagnosis of somatic disease; 26 27 11 (3) patients without systemic disease that can account for their physical discomfort; and (4) patients 28 29 12 enrolled as outpatients after they agree to complete the questionnaires and undergo assessment by 30 31 13 32 a physician will meet the inclusion criteria. 33 34 14 Exclusion criteria 35 36 37 15 (1) Patients who have lost their self-assessment ability or refuse to participate; (2) patients who http://bmjopen.bmj.com/ 38 39 16 have been previously confirmed to have mental disorders, mental retardation or dementia; (3) 40 41 17 patients who are taking anti-anxiety agents or anti-depression agents; and (4) patients who are 42 43 44 18 deemed unable to complete face-to-face follow-up after at least 1 month (such as those who live 45 on September 25, 2021 by guest. Protected copyright. 46 19 abroad) will be excluded from the study. 47 48 20 49 Reference standard 50 51 21 Patients were interviewed by a standard procedure. A structured clinical interview (SCID-5-CV) 52 53 22 according to the corresponding DSM-5 criterion was used by the physician. The interview 54 55 56 23 questions include modules from somatic symptom and related disorder to depression disorder, 57 58 24 anxiety disorder, obsessive-compulsive related disorder and sleep-wake disorders. The test time is 59 60 25 approximately 30-45 minutes. The physician further assesses the severity based on the number of
9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 24
1 2 3 1 symptoms specified in excessive thoughts, feeling, or behaviours related to the somatic symptoms BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 or associated health concerns (mild-1 symptom; moderate-two or more of the symptoms; severe- 7 8 3 two or more of the symptoms plus multiple somatic complaints). The physician assessment is set 9 10 4 as the reference standard. The physician team is composed of both general hospital “specified 11 12 5 physicians” (that is, physicians qualified as national psychological counsellors) and psychologists. 13 14 6 15 When there is diagnostic uncertainty, the patient will be referred to the senior physician to obtain 16 17 7 a diagnosis. 18 For peer review only 19 8 Obtaining informed consent 20 21 22 9 The trained researched will give the patients informed consent and provide all necessary 23 24 10 information about this study to the potential participants. It will be made clear to participants that 25 26 27 11 they are under no obligation to take part, their usual care will not be affected by their decision, and 28 29 12 they can withdraw consent without giving a reason. Participants will be given a sheet with contact 30 31 13 details for the research team and instructions on what to do if they wish to withdraw or require 32 33 14 further information. 34 35 36 15 Blinding 37 http://bmjopen.bmj.com/ 38 39 16 After a patient with suspected SSD is transferred to the specialist clinic, the patient will first 40 41 17 complete the questionnaires in a separate room, and the research assistant will help the patient 42 43 18 understand the questions. Then, an initial consultation will be blindly conducted by a physician 44 45 19 who has been qualified as a national psychological counsellor. An independent diagnosis and on September 25, 2021 by guest. Protected copyright. 46 47 48 20 severity category will be assigned by the physician. The duration of the self-reported scale and the 49 50 21 physician assessment will be separately recorded. 51 52 53 22 Medication 54 55 23 The patients will be informed of the results immediately after the physician consultation and the 56 57 24 58 questionnaire completion. During the follow-up consultations, the patients will be allowed to 59 60 25 communicate with the doctor throughout the diagnosis and treatment. Because patients in China
10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 24 BMJ Open
1 2 3 1 usually refuse to accept psychotherapy4 17, medications will be prescribed according to the BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 physician’s evaluation. Anti-anxiety treatment or anti-depression treatment will be selectively 7 8 3 administered according to the severity of the somatic symptom burden. Generally, members of 9 10 4 the thioxanthene class, such as Deanxit, are used for mild symptoms; selective serotonin reuptake 11 12 5 inhibitors (SSRIs) are applied for moderate symptoms; and serotonin-norepinephrine reuptake 13 14 6 15 inhibitors (SNRIs) are applied for severe symptoms, with the serotonin antagonist and reuptake 16 17 7 inhibitor (SARI) class prescribed if sleeping problems exist. 18 For peer review only 19 8 Follow-up 20 21 22 9 A face-to-face interview will be scheduled at 2, 6, and 10 weeks for patients taking medication. 23 24 10 The subject will complete 5 questionnaires (SSS-CN, PHQ15, PHQ-9, GAD-7 and SF-20) both 25 26 27 11 at the initial consultation and at the week 10 follow-up. The SF-20 survey aimed to evaluate quality 28 29 12 of life. At the week 2 and week 6 follow ups, 4 questionnaires will be completed (SSS-CN, PHQ15, 30 31 13 PHQ-9, GAD-7). 32 33 34 14 Outcome Measures 35 36 15 Reliability and validity 37 http://bmjopen.bmj.com/ 38 39 16 Reliability will be measured by Cronbach’s alpha. A randomized sample of approximately 100 40 41 17 participants will be asked to complete the questionnaires 1 week after the initial completion to 42 43 44 18 analyse the test-retest reliability. 45 on September 25, 2021 by guest. Protected copyright. 46 19 The criterion validity will be determined by assessment of the presence and severity of SSD 47 48 20 49 between the reference standard (physician assessment based on structure interview) and the SSS- 50 51 21 CN questionnaire. 52 53 22 The SSS-CN consists of 10 questions for somatic symptoms, 4 for depression, 4 for anxiety, and 54 55 56 23 2 for depression and anxiety. The construct validity will be tested by confirmatory factor analysis, 57 58 24 comparing the corresponding factors with the PHQ-15, PHQ-9 and GAD-7. 59 60
11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 24
1 2 3 1 Diagnostic performance BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 The diagnostic accuracy of a questionnaire for SSD identification is measured by the area under 7 8 3 the curve (AUC) of an ROC, the sensitivity/specificity under a prespecified cut-off value, and the 9 10 4 positive/negative predictive values in the study population, referring to the physician diagnosis as 11 12 13 5 the reference standard. The accuracy of the severity assessment of a questionnaire is measured by 14 15 6 the VUS (volume under the surface), which is a multi-class generalization of AUC of ROC between 16 17 7 the questionnaire score and the physician’s severity assessment18. 18 For peer review only 19 20 8 Other Clinical utilities 21 22 9 23 Convenience in clinical practice is measured by the average time taken to complete each 24 25 10 questionnaire or receive a diagnosis from a physician. 26 27 11 Clinical utility in monitoring treatment efficacy in patients is measured by correlation with the SF- 28 29 30 12 20 during follow-up visits. 31 32 13 Sample Size Calculation 33 34 35 14 The sample size calculation considers the comparison of diagnostic accuracy for both SSD 36 37 15 identification and severity assessment, whichever is larger. In the pilot study, the prevalence of http://bmjopen.bmj.com/ 38 39 16 40 SSD was 76.9% in the study population who were referred to the special clinics (where physicians 41 42 17 qualified as national psychological counsellors and psychologists practice medicine), the AUC of 43 44 18 the ROC for PHQ-15 was 0.88, and the VUS of multi-class ROC for PHQ-15 score with respect 45 on September 25, 2021 by guest. Protected copyright. 46 19 to the severity assessment was 0.7. The correlation between the SSS-CN and PHQ-15 scores was 47 48 20 49 set to 0.6. With a non-inferiority margin of 0.05, α=0.025, and β=0.8, the sample size for SSD 50 51 21 diagnosis was 852. With a non-inferiority margin of 0.1, α=0.025, and β=0.8, the sample size for 52 53 22 severity assessment was 517. Therefore, as the overall sample size of this study was N=852 with 54 55 23 SSD-positive N+=655 and SSD-negative N-=197, both the positive and negative sample size 56 57 24 58 requirements were met. 59 60 25 Statistical Analysis
12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 24 BMJ Open
1 2 3 1 We will report our results according to STARD. We will compute the median (P25, P75) scores BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 for each questionnaire and the number and percentage of patients (%) in each diagnostic category 7 8 3 as descriptive statistics. 9 10 4 Reliability will be measured using Cronbach’s α. The criterion validity will be measured by the 11 12 13 5 kappa coefficient between the questionnaire score and the physician assessment. Construct validity 14 15 6 will be tested using confirmatory factor analyses. 16 17 7 18 The primary analysisFor of the peer diagnostic performancereview will only consist of two comparisons using 19 20 8 Bonferroni’s correction: (1) the non-inferior comparison of the SSS-CN with the PHQ-15 in SSD 21 22 9 diagnostic accuracy as measured by the AUC of the ROC with =0.05, =0.025 in the whole 23 24 19 25 10 study population using Delong’s method and (2) Severity of PHQ-15 were based on scores, 26 27 11 normal (score 0–4), low (score 5–9), medium (score 10–14), and high (score 15–30). SSS-CN 28 29 12 scores range from 20 to 29, 30 to 39, 40 to 59, and ≥60 and represent normal, mild, moderate, and 30 31 13 severe SSD, respectively. The non-inferior comparison of the SSS-Ch with the PHQ-15 in SSD 32 33 34 14 severity assessment measured by VUS with =0.1, =0.025 in the population with a confirmed 35 36 15 SSD diagnosis using Z test 18. Both comparisons refer to the physician’s diagnosis as the reference 37 http://bmjopen.bmj.com/ 38 16 standard. If either non-inferiority criterion is met, the corresponding superiority will be tested. 39 40 41 17 As a secondary analysis, the sensitivity, specificity, and positive and negative predictive values will 42 43 18 also be reported. Prespecified cut-off values will be validated. In addition, we will compare the 44 45 19 on September 25, 2021 by guest. Protected copyright. 46 time needed to complete each questionnaire and be diagnosed by a physician. In the follow-up 47 48 20 data, questionnaire scores by time will be demonstrated in a line chart with error bars. 49 50 21 Missing values will be imputed with multiple imputation under the assumption of MAR17. 51 52 53 22 Subgroup analysis according to gender and age will also be conducted. All statistical analyses will 54 55 23 be performed with R (version 3.5.1) 56 57 58 24 Patient and Public Involvement Statement 59 60
13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 24
1 2 3 1 Patients were involved at the design stage of the trial, including ensuring that the content of the BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 SSS-CN questionnaire can be understood, the length of the consultation time, the manner of 7 8 3 notification of the disease condition, the follow-up method, and the dissemination of the results 9 10 4 are acceptable. Before the formal recruitment started, we received feedback from patients who 11 12 5 had SSD during a pretest of the case report form (CRF) and used it to improve the final design 13 14 6 15 of the CRF. We carefully assessed the burden of the trial interventions on patients. We intend to 16 17 7 disseminate the main results to the trial participants via email. The study outcomes will be 18 For peer review only 19 8 disseminated in conference reports and academic publications. 20 21 22 9 Current Status 23 24 10 The first study participant was enrolled in November 2017. As of Mar 2019, patient recruitment 25 26 27 11 has not been completed. 28 29 12 30 31 32 13 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 24 BMJ Open
1 2 3 1 DISCUSSION BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 In this study protocol, we describe a diagnostic study design that evaluates the efficacy of a newly 7 8 3 developed somatic and psychological symptom scale adapted to China for patients with suspected 9 10 4 somatic diseases that might be applied as a first-line instrument for screening and monitoring 11 12 13 5 treatment efficacy in individual outpatient consultations. We expect that a physician will benefit 14 15 6 from the SSS-CN on a clinically significant level through improved self-confidence and timeliness 16 17 7 and that the participants will benefit by improving their awareness of the disease and ability to self- 18 For peer review only 19 8 monitor their symptoms. Moreover, we will examine the characteristics of the SSS-CN compared 20 21 22 9 with another somatic symptom questionnaire (PHQ15). 23 24 10 Our SSS-CN is designed as a “one-stop shop” tool that combines somatic items with mental 25 26 27 11 disorder items. This design is consistent with the suggestion in the DSM-5 that somatic symptoms 28 29 12 are likely accompanied by depression and anxiety1. Somatic and mental symptoms may interact, 30 31 13 and mental symptoms may be triggered differently than conventional mental diseases in this group. 32 33 14 Clinically, it is not easy to clearly separate the body from mental status, and the significance of each 34 35 36 15 item is unknown. We caution that 50% of mental items have the possibility of increasing the 37 http://bmjopen.bmj.com/ 38 16 incidence of SSD, and a subgroup score with somatic symptom items alone is used for this 39 40 17 appraisal. 41 42 43 18 The study has several strengths. First, we will introduce a tool to facilitate daily clinical work. The 44 45 19
tool provides clinicians with an easy-to-use questionnaire in screening suspected SSD patients and on September 25, 2021 by guest. Protected copyright. 46 47 20 to refer the patients to specific doctors. Second, our previous study has shown the reliability and 48 49 21 15 50 factorial validity of the SSS-CN by utilizing an early version of it . The current study further 51 52 22 modifies the SSS-CN based on the DSM-5 and, for the first time, evaluates its clinical utility. Third, 53 54 23 patients will benefit by improving their awareness of the disease and their ability to self-monitor 55 56 24 their symptoms. 57 58 59 60
15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 24
1 2 3 1 This trial has some limitations. First, SSD can be accompanied by diagnosed medical disorders. BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 The current study, however, represents the efficacy of the SSS-CN only in patients without 7 8 3 organic diseases. Therefore, further research on the application of SSS-CN in patients with both 9 10 4 SSD and diagnosed medical disorders is required. Moreover, the epidemiology of primary health 11 12 5 care facilities is different from the epidemiology of general hospitals; therefore, the diagnostic 13 14 6 15 accuracy in a health care sample needs additional investigation. Second, the study was designed 16 17 7 as a mid-term investigation with four measurement time points, and thus missing data must be 18 For peer review only 19 8 considered. Referring to the fact that only 16% of patients in the primary care evaluation of 20 21 9 mental disorders (PRIME-MD) study were involved in the follow-up18, we estimate that a high 22 23 10 24 rate of missing data will also occur in our patients. Because of the difficulty of compliance, only a 25 26 11 small fraction (16% by estimation) of patients in study would be involved in the follow-up, and 27 28 12 the result of monitoring the treatment effect may be affected by loss to follow-up bias. 29 30 31 13 This study will help to clarify whether the developed SSS-CN score is an effective tool for rapid 32 33 14 screening and assessment of severity in patients with suspected SSD in a general hospital clinic 34 35 15 and for convenient follow-up. If the SSS-CN is found to be effective, it can be implemented as a 36 37 16 first-line screening and follow-up option. Additionally, we expect that the SSS-CN could provide http://bmjopen.bmj.com/ 38 39 40 17 personalized information to consulting physicians in a timely manner. The study results will 41 42 18 contribute to better outpatient care for patients with SSD. 43 44 45 19 on September 25, 2021 by guest. Protected copyright. 46 47 20 48 49 50 51 52 53 54 55 56 57 58 59 60
16 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 24 BMJ Open
1 2 3 Acknowledgements: We thank all the patients who participated and advised us throughout the BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 study design and implementation for their contributions. 7 8 Conflict of interests: The authors declare that they have no competing interests. 9 10 Ethical approval: Ethical approval was provided by the Renji Hospital Human Research Ethics 11 12 Committee, approval number 2015016. 13 14 15 Consent for publication: All participants to date have provided written informed consent. 16 17 Authors' contributions: MJ: substantial contributions to the conception, design and 18 For peer review only 19 interpretation of data, drafting and critical revisions for important intellectual content. WTZ: 20 21 analysis, statistics and interpretation of data, drafting the manuscript. XS: design and 22 23 24 implementation of study, acquisition of data, analysis and interpretation of data, drafting the 25 26 manuscript. CG: analysis, statistics and interpretation of data. BXC: acquisition of data, analysis 27 28 and interpretation of data, drafting the manuscript. ZHF: acquisition of data, analysis and 29 30 interpretation of data, drafting the manuscript. JLM: substantial contributions to the conception, 31 32 33 design and interpretation of data, critical revisions for important intellectual content. JP: substantial 34 35 contributions to the conception, design and interpretation of data. 36 37
Funding: This work was supported by the National Natural Science Foundation of China http://bmjopen.bmj.com/ 38 39 (81470391 and 81470389); National Science Fund for Distinguished Young Scholars (81625002); 40 41 42 Shanghai ShenKang Hospital Development Center (16CR3020A and 16CR3034A); Shanghai 43 44 Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20172014 and 45 on September 25, 2021 by guest. Protected copyright. 46 20152209); Shanghai Outstanding Academic Leaders Program (18XD1402400); Shanghai Pudong 47 48 Health Development Center (PW2018D-03); Shanghai Jiaotong University (YG2016MS45 and 49 50 51 YG2015ZD04). 52 53 Registration name: The validation and utility of the Somatic Symptom Scale-China (SSS-CN) for 54 55 assessing somatic symptom disorder in general hospital outpatients. 56 57 58 59 60
17 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 24
1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 1. Barsky AJ, Orav EJ, Bates DW. Somatization increases medical utilization and costs 7 independent of psychiatric and medical comorbidity. Archives of general psychiatry 8 2005;62(8):903-10. doi: 10.1001/archpsyc.62.8.903 9 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 10 Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Association Publishing 11 2013. 12 3. Barsky AJ. Assessing somatic symptoms in clinical practice. JAMA Intern Med 13 2014;174(3):407-8. doi: 10.1001/jamainternmed.2013.12177 14 4. Liang D, Mays VM, Hwang WC. Integrated mental health services in China: challenges 15 and planning for the future. Health Policy Plan 2018;33(1):107-22. doi: 16 10.1093/heapol/czx137 17 5. Jr SG. The course of somatization and its effects on utilization of health care resources. 18 For peer review only 19 Psychosomatics 1994;35(3):263. 20 6. Hahn SR, Kroenke K, Spitzer RL, et al. The difficult patient: prevalence, psychopathology, 21 and functional impairment. Journal of General Internal Medicine 1996;11(1):1. 22 7. Laferton JAC, Stenzel NM, Rief W, et al. Screening for DSM-5 Somatic Symptom 23 Disorder: Diagnostic Accuracy of Self-Report Measures Within a Population Sample. 24 Psychosom Med 2017;79(9):974-81. doi: 10.1097/PSY.0000000000000530 25 8. Axelsson E, Andersson E, Ljotsson B, et al. The health preoccupation diagnostic 26 interview: inter-rater reliability of a structured interview for diagnostic assessment of 27 DSM-5 somatic symptom disorder and illness anxiety disorder. Cogn Behav Ther 28 2016;45(4):259-69. doi: 10.1080/16506073.2016.1161663 29 9. Gierk B, Kohlmann S, Kroenke K, et al. The somatic symptom scale-8 (SSS-8): a brief 30 measure of somatic symptom burden. JAMA Intern Med 2014;174(3):399-407. doi: 31 10.1001/jamainternmed.2013.12179 32 10. Gierk B, Kohlmann S, Toussaint A, et al. Assessing somatic symptom burden: a 33 psychometric comparison of the patient health questionnaire-15 (PHQ-15) and the 34 somatic symptom scale-8 (SSS-8). J Psychosom Res 2015;78(4):352-5. doi: 35 10.1016/j.jpsychores.2014.11.006 36 11. Tu CY, Liao SC, Liu CY, et al. Application of the Chinese Version of the Whiteley Index-7 37 for Detecting DSM-5 Somatic Symptom and Related Disorders. Psychosomatics http://bmjopen.bmj.com/ 38 39 2016;57(3):283-91. doi: 10.1016/j.psym.2015.12.010 40 12. Toussaint A, Murray AM, Voigt K, et al. Development and Validation of the Somatic 41 Symptom Disorder-B Criteria Scale (SSD-12). Psychosom Med 2016;78(1):5-12. doi: 42 10.1097/PSY.0000000000000240 43 13. Toussaint A, Lowe B, Brahler E, et al. The Somatic Symptom Disorder - B Criteria Scale 44 (SSD-12): Factorial structure, validity and population-based norms. J Psychosom 45 Res 2017;97:9-17. doi: 10.1016/j.jpsychores.2017.03.017 on September 25, 2021 by guest. Protected copyright. 46 14. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use: 47 Guideline on clinical evaluation of diagnostic agents. 48 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/0 49 9/WC500003584.pdf. 50 15. Qi Z, Jialiang M, Chunbo L, et al. Developing of somatic self-rating scale and its reliability 51 and validity. Chinese Journal of Behavioral Medicine and Brain Science 52 2010;19(9):847-9. 53 16. Organization WH. The ICD-10 Classification of Mental and Behavioural Disorders: 54 Clinical Description and Diagnostic Guidelines: WHO 1993. 55 17. Leong FT, Lau AS. Barriers to providing effective mental health services to Asian 56 Americans. Ment Health Serv Res 2001;3(4):201-14. 57 58 18. Nakas CT, Yiannoutsos CT. Ordered multiple-class ROC analysis with continuous 59 measurements. Stat Med 2004;23(22):3437-49. doi: 10.1002/sim.1917 60
18 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 24 BMJ Open
1 2 3 19. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 correlated receiver operating characteristic curves: a nonparametric approach. 5 Biometrics 1988;44(3):837-45. 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
19 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 24
1 2 3 Figure Legends BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 Figure 1 The Somatic Symptom Scale-China (SSS-CN). 7 8 9 Figure 2 Study flow. SSS-CN, Somatic Symptom Scale-China; PHQ-15: Patient Health 10 11 Questionnaire-15; PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety 12 13 Disorder Scale-7; SF-20: 20-Item Short Form Health Survey; SSD: Somatic Symptom Disorder. 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
20 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 Figure 1 46 47 210x297mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 24 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 Figure 2 26 27 338x190mm (300 x 300 DPI) 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 24 BMJ Open
1 2 3 TITLE OR BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 PageABSTRACT 1, line 1-2 1 Identification as a study of diagnostic accuracy using at least one measure 5 of accuracy (such as sensitivity, specificity, predictive values, or AUC) 6 ABSTRACT 7 Page 2, line 2-18 for 2 Structured summary of study design, methods, results, and conclusions 8 protocol article 9 (for specific guidance, see STARD for Abstracts) 10 INTRODUCTION 11 Page 4-5, line 2-21 3 Scientific and clinical background, including the intended use and clinical 12 role of the index test 13 Page 5, line 22-page 6, 4 Study objectives and hypotheses 14 line3; Page 6,line 17-page 15 7, line 3 16 METHODS 17 Study design 5 Whether data collection was planned before the index test and reference 18 Page 8, line 3; Page For14,line peerstandard reviewwere performed (prospectiveonly study) or after (retrospective study) 19 13-22 20 Participants 6 Eligibility criteria 21 Page 10,line 1-11 22 Page 9,line 12-16 7 On what basis potentially eligible participants were identified 23 (such as symptoms, results from previous tests, inclusion in registry) 24 Page 9, line 12-21 8 Where and when potentially eligible participants were identified (setting, 25 location and dates) 26 Page 9, line 12 9 Whether participants formed a consecutive, random or convenience series 27 Test methods 10a Index test, in sufficient detail to allow replication 28 Page 8,line 12-page 9, 29 line 6; Figure 1 30 Page 10,line 12-19;Suppl 31 10b Reference standard, in sufficient detail to allow replication Fig1 32 33 Page 4,line 23-page 5, line 11 Rationale for choosing the reference standard (if alternatives exist) 34 5 35 Page 8,line 19-page 9,line 12a Definition of and rationale for test positivity cut-offs 36 6 or result categories of the index test, distinguishing 37 Suppl Fig1 12b pre-specifiedDefinition of andfrom rationale exploratory for test positivity cut-offs or result categories http://bmjopen.bmj.com/ 38 of the reference standard, distinguishing pre-specified from exploratory 39 Page 9, line 18-21 13a Whether clinical information and reference standard results were 40 available 41 Page 9, line 16-18; Page 13b Whetherto the performers/readers clinical information of the and index index test test results were available 42 12, line 1-3 43 to the assessors of the reference standard 44 Analysis 14 Methods for estimating or comparing measures of diagnostic accuracy 45 Page12，line 15-21 ， 15 How indeterminate index test or reference standard results were handled on September 25, 2021 by guest. Protected copyright. 46 Page10 line 19 47 Page 14,line 10-12 16 How missing data on the index test and reference standard were handled 48 Page12，line 15-21 17 Any analyses of variability in diagnostic accuracy, distinguishing pre- 49 specified from exploratory 50 Page 13, line 3-13 18 Intended sample size and how it was determined 51 RESULTS 52 Participants 19 Flow of participants, using a diagram 53 54 NA 20 Baseline demographic and clinical characteristics of participants 55 NA 21a Distribution of severity of disease in those with the target condition 56 NA 21b Distribution of alternative diagnoses in those without the target condition 57 NA 22 Time interval and any clinical interventions between index test and 58 reference standard 59 Test results 23 Cross tabulation of the index test results (or their distribution) 60 by the results of the reference standard
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 24
1 2 3 NA 24 Estimates of diagnostic accuracy and their precision (such as 95% BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 confidence intervals) 6 NA 25 Any adverse events from performing the index test or the reference 7 standard 8 DISCUSSION 9 Page 17,line 1-16 26 Study limitations, including sources of potential bias, statistical 10 uncertainty, and generalisability 11 Page 16,line 2-9;line 18- 27 Implications for practice, including the intended use and clinical role of 12 25; Page 17,line 17-22 the index test 13 OTHER 14 PageINFORMATION 2,line 24;Page 28 Registration number and name of registry 15 18,line 23-24； 16 NA 29 Where the full study protocol can be accessed 17 Page 18,line 15-22 30 Sources of funding and other support; role of funders 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
Research Protocol for a Diagnostic Study: Identifying and Measuring the Severity of Somatic Symptom Disorder Using the Self-reported Somatic Symptom Scale-China (SSS-CN) ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024290.R3
Article Type: Protocol
Date Submitted by the 04-Jul-2019 Author:
Complete List of Authors: Jiang, Meng; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Zhang, Weituo; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Su, Xuan; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Gao, Chuang; Clinical Research Center, School of Medicine, Shanghai Jiaotong University Chen, Bingxu; School of Medicine, Shanghai Jiao Tong University Feng, Zehao; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology Mao, Jialiang; Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology http://bmjopen.bmj.com/ Pu, Jun; Renji Hospital, School of Medicine, Shanghai Jiaotong University
Primary Subject Mental health Heading:
Secondary Subject Heading: Research methods
Somatic Symptom Scale-China, somatic symptom disorder, mental Keywords: disorders management on September 25, 2021 by guest. Protected copyright.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 26 BMJ Open
1 2 3 1 Research Protocol for a Diagnostic Study: Identifying and Measuring the Severity of BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 Somatic Symptom Disorder Using the Self-reported Somatic Symptom Scale-China (SSS- 7 8 3 CN) 9 10 4 11 12 5 Meng Jianga1, MD, PhD, Weituo Zhanga2, PhD, Xuan Su1, MD, Chuang Gao2, MPH, Bingxu 13 14 3 1 *1 *1 15 6 Chen , MD, Zehao Feng , MD, Jialiang Mao , MD, PhD, Jun Pu , MD, PhD 16 17 7 18 For peer review only 19 8 1 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 20 21 9 Shanghai, China 200127; 2 Clinical Research Center, School of Medicine, Shanghai Jiao Tong 22 23 3 24 10 University, Shanghai, China 200025; School of Medicine, Shanghai Jiao Tong University, 25 26 11 Shanghai, China 200025 27 28 12 29 30 13 a Co-first author: Meng Jiang and Weituo Zhang contributed equally to the paper. 31 32 33 14 * Names and addresses correspondence: Jialiang Mao, MD, PhD; Jun Pu, MD, PhD, FACC, 34 35 15 FESC; Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong 36 37 16 University, Shanghai, China; 160 Pujian Road, Shanghai, China, 200127. Tel: 086-21-68383447, http://bmjopen.bmj.com/ 38 39 17 Fax: 086-21-68383447; Email: [email protected]; [email protected]. 40 41 42 18 43 44 19 Word count: 5103 45 on September 25, 2021 by guest. Protected copyright. 46 20 47 21 48 49 50 51 52 53 54 55 56 57 58 59 60
1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 26
1 2 3 1 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Introduction The detection rate of somatic symptom disorder (SSD) in general hospitals is 7 8 3 unsatisfactory. Self-report questionnaires that assess both somatic symptoms and psychological 9 10 4 characteristics will improve the process of screening for SSD. The Somatic Symptom Scale-China 11 12 13 5 (SSS-CN) questionnaire has been developed to meet this urgent clinical demand. The aim of this 14 15 6 research is to validate the self-reported SSS-CN as a timely and practical instrument that can be 16 17 7 used to identify SSD and to assess the severity of this disorder. 18 For peer review only 19 20 8 Methods and Analysis At least 852 patients without organic disease but presenting physical 21 22 9 discomfort will be recruited at a general hospital. Each patient will undergo a DSM-5-guided 23 24 10 physician diagnosis, including disease identification and severity assessment, as the reference 25 26 27 11 standard. This research will compare the diagnostic performance of the SSS-CN for SSD, the 28 29 12 Patient Health Questionnaire-15 (PHQ-15) and other SSD-related questionnaires. Statistical tests 30 31 13 to measure the area under the curve (AUC) and volume under the surface (VUS) of the receiver 32 33 14 operating curve (ROC) will be used to assess the accuracy of the SSD identification and the 34 35 36 15 severity assessment, respectively. In addition to this standard diagnostic study, we will conduct 37 http://bmjopen.bmj.com/ 38 16 follow-up investigations to explore the effectiveness of the SSS-CN in monitoring treatment 39 40 17 effects. 41 42 18 43 44 45 19 on September 25, 2021 by guest. Protected copyright. 46 47 20 Ethics and Dissemination Ethical approval was obtained from the Renji Hospital Human 48 49 21 50 Research Ethics Committee, approval number 2015016. The findings of this study will be 51 52 22 disseminated via peer-reviewed journals and presented at international conferences. 53 54 23 Trial registration number: NCT03513185 55 56 57 24 58 59 60
2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 26 BMJ Open
1 2 3 1 Strengths and Limitations of this Study BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 1. The Somatic Symptom Scale-China (SSS-CN) questionnaire is developed according to the 7 8 3 DSM-5, and its clinical utility is evaluated herein for the first time. 9 10 11 4 2. The SSS-CN will benefit patients by improving their awareness of SSD and their ability to self- 12 13 5 monitor their symptoms. 14 15 16 6 3. The SSS-CN will provide clinicians with an easy-to-use tool that can be completed quickly and 17 18 7 assess both somaticFor and psychologicalpeer reviewcomponents. only 19 20 21 8 4. Referral bias may be present in this study, as only patients without organic disease will be 22 23 9 referred to our special clinic. 24 25 26 10 5. Treatment effect monitoring will be affected by the bias due to non-random loss to follow-up. 27 28 11 29 30 31 12 Keywords 32 33 34 13 Somatic Symptom Scale-China; somatic symptom disorder; mental disorders management 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 26
1 2 3 1 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Somatic symptom disorder (SSD) 1 2 is a common medical condition observed in general 7 8 3 hospitals. SSD is characterized by symptoms that are often difficult to explain after adequate 9 10 4 evaluation3; even when a significant medical disease is present, the patients’ symptoms may 11 12 2 13 5 nonetheless be unrelated to their disease . The diagnosis of SSD emphasizes the existence of 14 15 6 symptoms and signs (one or multiple somatic symptoms, and abnormal thoughts, feelings, and 16 17 7 behaviours in response to these symptoms)2. The current prevalence of this disorder is estimated 18 For peer review only 19 2 4 20 8 to be 5-7% in the general population, and it may be even higher in Asian individuals . 21 22 9 In general hospitals, the detection rate of SSD is unsatisfactory due to the diagnostic complexity 23 24 10 of the disease and the lack of adequate training for physicians to evaluate patients with suspected 25 26 11 27 SSD. Therefore, patients may sustain somatic symptoms without appropriate treatment due to 28 29 12 the unawareness of SSD. The yearly cost of medical care among patients with somatization is 30 31 13 nearly twice as high as the yearly cost among patients without somatization. An estimated $256 32 33 14 billion in annual medical care costs is attributable to the incremental effects of somatization 34 35 15 1 36 alone . Hence, it is highly important that physicians are trained to identify SSD, assess the 37 http://bmjopen.bmj.com/ 38 16 symptom severity and treat it in a timely manner; failure to do so can result in high morbidity, 39 40 17 lost productivity, and overutilization of medical resources5 6. However, compared to widely 41 42 18 researched disorders such as depression and anxiety, SSD has been far less studied. Follow-up or 43 44 19 45 treatment studies of this disorder are even scarcer. on September 25, 2021 by guest. Protected copyright. 46 47 20 It is more favourable to have a tool for screening patients suspected of having SSD via accurate 48 49 21 and brief diagnostic questionnaires and to facilitate daily clinical work. One of the aims of the 50 51 22 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is to identify 52 53 23 2 54 SSD patients and to assess the severity of the disorder . The DSM-5 states that SSD comorbid 55 56 24 with anxiety and depressive disorder (a combination present in approximately 57.7% of SSD 57 58 25 patients)1 adds severity and complexity to the somatic components. The DSM-5 emphasizes that 59 60 26 it is important to evaluate patients in terms of their psychological situation, behaviour and
4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 26 BMJ Open
1 2 3 1 physical condition altogether and then treat the patients according to the severity of the disorder. BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 Furthermore, the DSM-5 emphasizes the evaluation of subjects who have excessive concerns 7 8 3 about health issues. However, the DSM-5 is clinically difficult to follow because it requires 9 10 4 qualified and experienced physicians to conduct an interview7, which makes clinicians in general 11 12 5 hospitals feel less confident when treating patients who are suspected to have SSD. In particular, 13 14 6 4 8 15 individuals in China and other Asian countries tend to refuse psychological counselling ; thus, 16 17 7 many patients with psychological symptoms have been treated by non-psychiatric physicians in 18 For peer review only 19 8 general medical hospitals. A series of studies has focused on this issue; the Patient Health 20 21 9 Questionnaire-15 (PHQ-15) and the Somatic Symptom Scale-8 are screening tools for SSD9 10; 22 23 10 24 however, these self-report questionnaires do not assess psychological features. The Whiteley 25 11 26 11 Index-7 focuses on health anxiety ; the Scale for the Assessment of Illness Behavior 27 28 12 questionnaires focuses on excessive illness behaviour; and the Somatic Symptom Scale-12 29 30 13 assesses psychological features12 13. The latter three questionnaires focus less on physical features. 31 32 14 33 Recent studies, including one by Laferton et al., have indicated that self-report measures that 34 14 35 15 focus on different aspects could increase diagnostic quality in clinical practice . 36 37 16 Based on published studies, we aim to develop a comprehensive questionnaire to assess somatic http://bmjopen.bmj.com/ 38 39 40 17 symptoms of SSD comorbid with anxiety and depression symptoms. The Somatic Symptom Scale- 41 42 18 China (SSS-CN) questionnaire was developed based on the DSM-5. The questionnaire assesses a 43 44 19 combination of psychological, behavioural, and somatic symptoms. The questionnaire was 45 on September 25, 2021 by guest. Protected copyright. 46 20 designed for use in general medical facilities and to provide clinicians with an easy-to-use 47 48 49 21 questionnaire for detecting both somatic and psychological features in a timely manner. 50 51 22 Study Objectives and Research Questions 52 53 54 23 Primary objective 55 56 57 58 59 60
5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 26
1 2 3 1 The primary objective of this study is to test two aspects of the diagnostic accuracy of the SSS-CN BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 compared with the PHQ-15, with a DSM-5-guided physician diagnosis as the reference standard: 7 8 3 (1) the accuracy for identifying SSD and (2) the accuracy for assessing SSD severity. 9 10 4 Secondary objective 11 12 13 5 The secondary objective is to explore the potential utility of the SSS-CN in monitoring the 14 15 6 treatment effect. We aim to examine how the scores of the SSS-CN and other questionnaires 16 17 7 18 change over time afterFor treatment. peer review only 19 20 8 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 26 BMJ Open
1 2 3 1 METHODS BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 Study Overview 7 8 9 3 This study will use a prospective diagnostic design and will be conducted at a tertiary general 10 11 4 hospital in Shanghai, China. The study protocol was approved by the ethics committees of Renji 12 13 5 Hospital, and written informed consent will be obtained from all study participants. The clinical 14 15 6 trial registration can be found at https://register.clinicaltrials.gov/, and the registration number is 16 17 7 18 NCT03513185. For peer review only 19 20 8 Particular attention will be paid to the appropriate storage of the data. Patient confidentiality will 21 22 9 23 be maintained, and no identifying characteristics of the patients will be published. The protocol 24 15 25 10 development will adhere to the European Medicines Agency guidelines for diagnosis study . 26 27 11 Description of the SSS-CN and Assessment of Severity 28 29 30 12 The SSS-CN is a somatic and psychological symptom scale (Figure 1) derived from the DSM-5. 31 32 13 It is designed to assess the presence and severity of the symptoms. We validated its reliability and 33 34 16 35 14 validity in a previous study . The test-retest reliability was 0.9. The correlation coefficients 36 37 15 between each dimension and the total ranged from 0.76-0.88, and the correlation coefficients http://bmjopen.bmj.com/ 38 39 16 within dimensions ranged from 0.56-0.70. 40 41 42 17 The questionnaire is self-administered with an abbreviated 20-item measure. Briefly, in the 43 44 18 previous study, the SSS-CN was composed of 4 dimensions: physical disorder, anxiety disorder, 45 on September 25, 2021 by guest. Protected copyright. 46 19 depression disorder, and anxiety and depression disorder. Half of the items ask about physical 47 48 20 49 complaints (1 item per body system, items 1, 5, 9, 10, 12, 13, 16, and 18-20). The remaining items 50 51 21 ask about anxiety and depression (anxiety items 6, 14, 15, and 17; depression items 3, 4, 7, and 11; 52 53 22 and anxiety and depression items 2 and 8). Subjects answer the following question: “Since you 54 55 23 have felt unwell, how often have you been bothered in the previous 6 months by any of the 56 57 24 58 following problems?” For scoring, the subjects rate the frequency of each symptom using the 59 60 25 following response options: 1 (“does not exist”), 2 (“the problem occurred occasionally for a
7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 26
1 2 3 1 couple of days per month and/or is endurable”), 3 (“the problem occurred almost half of the days BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 per month and/or I hope it will ease up”) or 4 (“the problem occurred almost every day and/or is 7 8 3 unendurable”). Thus, in determining the SSS-CN score, each question has a score ranging from 1 9 10 4 to 4, corresponding to the frequency of the problem occurrence, and the total score ranges from 11 12 5 20 to 80. The severity of SSD is determined based on the sum of the scores. SSS-CN scores ranging 13 14 6 15 from 20-29, 30-39, 40-59, and ≥60 correspond to normal, mild, moderate, and severe SSD, 16 17 7 respectively. The selection of the cutoff value of 30 is based on the results of our previous study 18 For peer review only 19 8 (It was obtained from the receiver operating curve (ROC), reaching a sensitivity of 0.97 and a 20 21 9 specificity of 0.96)16. Other cut-offs (40,60) are chosen based on clinical experience rather than 22 23 10 24 previous research. 25 26 11 Study Design 27 28 29 12 The study is composed of 2 stages (Figure 2) corresponding to the primary and secondary research 30 31 13 objectives. The first stage is a prospective diagnostic stage to assess the diagnostic performance of 32 33 14 the SSS-CN questionnaire. The second stage is an exploratory follow-up stage that uses the SSS- 34 35 36 15 CN questionnaire as a tool to monitor treatment effects. 37 http://bmjopen.bmj.com/ 38 16 Briefly, consecutive outpatients with physical discomfort presenting to internal medicine 39 40 17 41 departments in a tertiary hospital in China will first undergo the corresponding examination to 42 43 18 exclude organic disease. For example, a patient with chest pain will be recommended by a physician 44 45 19
to receive an EKG, echocardiography, a treadmill test or coronary angiography to exclude on September 25, 2021 by guest. Protected copyright. 46 47 20 cardiovascular disease. Patients with no organic disease that can account for their discomfort will 48 49 21 50 be considered to have a probable psychosomatic disorder. These patients will then be transferred 51 52 22 to a specialist clinic for the diagnosis and treatment of suspected SSD (the initial consultation). 53 54 23 They will fill out the SSS-CN questionnaire; they will also complete other self-reported 55 56 24 instruments, including the PHQ15, the Patient Health Questionnaire-9 (PHQ-9), the Generalized 57 58 25 59 Anxiety Disorder Scale-7 (GAD-7) and the SF-20, to verify the structural validity of SSS-CN. Non- 60
8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 26 BMJ Open
1 2 3 1 clinical research assistants will collect the questionnaires and calculate the scores. A physician or a BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 psychologist who is blind to the results of the SSS-CN will separately interview the patient to 7 8 3 diagnose SSD using the standard interview criteria put forth in the DSM-5. Prescriptions will be 9 10 4 given if the patient is diagnosed with SSD. For patients receiving medications, follow-up visits will 11 12 5 be scheduled at 2, 6, and 10 weeks to repeat the questionnaires (the follow-up consultation). 13 14 6 15 Because health-related quality of life is often impaired in patients with SSD, the 20-item Short 16 17 7 Form Health Survey (SF-20) will be administered as an indicator of therapeutic effects during 18 For peer review only 19 8 follow-up. 20 21 22 9 Participants and Procedure 23 24 10 Inclusion criteria 25 26 27 11 (1) Patients aged 18-80 years old; (2) patients who have no previous diagnosis of somatic disease; 28 29 12 (3) patients without systemic disease that can account for their physical discomfort; and (4) patients 30 31 13 32 enrolled as outpatients after they agree to complete the questionnaires and undergo assessment by 33 34 14 a physician. 35 36 15 Exclusion criteria 37 http://bmjopen.bmj.com/ 38 39 16 (1) Patients who have lost their self-assessment ability or refuse to participate; (2) patients who 40 41 17 have been confirmed to have mental disorders, mental retardation or dementia; (3)patients who 42 43 44 18 currently take anti-anxiety agents or anti-depression agents; and (4) patients who are unable to 45 on September 25, 2021 by guest. Protected copyright. 46 19 complete face-to-face follow-up visits after at least 1 month. 47 48 20 49 Reference standard 50 51 21 Patients will be interviewed using the standard procedure. The physician will conduct a structured 52 53 22 clinical interview (SCID-5-CV) in accordance with the corresponding DSM-5 criterion. The 54 55 56 23 interview questions include modules from somatic symptom and related disorder to depression 57 58 24 disorder, anxiety disorder, obsessive-compulsive related disorder and sleep-wake disorders. The 59 60 25 interview will last approximately 30-45 minutes. The physician will assess the severity based on the
9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 26
1 2 3 1 number of symptoms, i.e., excessive thoughts, feelings, or behaviours related to the somatic BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 symptoms or associated health concerns (mild: one symptom; moderate: two or more of the 7 8 3 symptoms; severe: two or more of the symptoms plus multiple somatic complaints). The physician 9 10 4 assessment will be used as the reference standard. The physician team will be composed of both 11 12 5 general hospital “specified physicians” (that is, physicians qualified as national psychological 13 14 6 15 counsellors) and psychologists. When there is diagnostic uncertainty, the patient will be referred 16 17 7 to the senior physician to obtain a diagnosis. 18 For peer review only 19 8 Obtaining informed consent 20 21 22 9 A trained researcher will obtain informed consent and provide all necessary information about this 23 24 10 study to the potential participants. It will be made clear to participants that they are under no 25 26 27 11 obligation to take part, their usual care will not be affected by their decision, and they can withdraw 28 29 12 consent without giving a reason. Participants will be given a sheet with contact details for the 30 31 13 research team and instructions on what to do if they wish to withdraw or require further 32 33 14 information. 34 35 36 15 Blinding 37 http://bmjopen.bmj.com/ 38 39 16 After a patient with suspected SSD is transferred to the specialist clinic, the patient will first 40 41 17 complete the questionnaires in a separate room, and the research assistant will help the patient 42 43 18 understand the questions. Then, an initial consultation will be conducted by a physician who has 44 45 19 been qualified as a national psychological counsellor and who has been blinded to the patient’s on September 25, 2021 by guest. Protected copyright. 46 47 48 20 responses to the SSS-CN. An independent diagnosis and severity assessment will be made by the 49 50 21 physician. The durations of the self-reported scale and the physician assessment will be recorded 51 52 22 separately. 53 54 55 23 Medication 56 57 24 58 The patients will be informed of the results immediately after the physician consultation and the 59 60 25 questionnaire. During the follow-up consultations, the patients will be allowed to communicate
10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 26 BMJ Open
1 2 3 1 with the doctor throughout the diagnosis and treatment. Because patients in China usually refuse BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 4 8 6 to accept psychotherapy , medications will be prescribed according to the physician’s evaluation. 7 8 3 Anti-anxiety treatment or anti-depression treatment will be selectively administered according to 9 10 4 the severity of the somatic symptoms. Generally, drugs that are classified as thioxanthenes, such 11 12 5 as Deanxit, are prescribed for mild symptoms; selective serotonin reuptake inhibitors (SSRIs) are 13 14 6 15 prescribed for moderate symptoms; and serotonin-norepinephrine reuptake inhibitors (SNRIs) are 16 17 7 prescribed for severe symptoms. Serotonin antagonist and reuptake inhibitors (SARIs) are 18 For peer review only 19 8 prescribed for sleeping problems. 20 21 22 9 Follow-up 23 24 10 A face-to-face interview will be scheduled at 2, 6, and 10 weeks for patients taking medication. 25 26 27 11 The patient will complete 5 questionnaires (SSS-CN, PHQ15, PHQ-9, GAD-7 and SF-20) both at 28 29 12 the initial consultation and at the week 10 follow-up. The SF-20 aims to evaluate the respondent’s 30 31 13 quality of life. At week 2 and week 6, the patient will complete 4 questionnaires (SSS-CN, PHQ15, 32 33 14 PHQ-9, GAD-7). 34 35 36 15 Outcome Measures 37 http://bmjopen.bmj.com/ 38 39 16 Reliability and validity 40 41 17 Reliability will be measured by Cronbach’s alpha. A randomized sample of approximately 100 42 43 44 18 participants will be asked to complete the questionnaires 1 week after the initial completion to 45 on September 25, 2021 by guest. Protected copyright. 46 19 analyse the test-retest reliability. 47 48 20 49 The criterion validity will be determined by comparing the presence and severity of SSD between 50 51 21 the reference standard (physician assessment based on structure interview) and the SSS-CN 52 53 22 questionnaire. 54 55 56 23 The SSS-CN consists of 10 items assessing somatic symptoms, 4 items assessing depression, 4 57 58 24 items assessing anxiety, and 2 items assessing depression and anxiety. The construct validity will 59 60
11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 26
1 2 3 1 be tested by confirmatory factor analysis, comparing the corresponding factors with the PHQ-15, BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 PHQ-9 and GAD-7. 7 8 3 Diagnostic performance 9 10 11 4 The diagnostic accuracy of a questionnaire for SSD identification is measured by the area under 12 13 5 the curve (AUC) of an ROC, the sensitivity/specificity under a prespecified cutoff value, and the 14 15 6 positive/negative predictive values in the study population, using the physician diagnosis as the 16 17 7 18 reference standard. TheFor accuracy peer of the severity review assessment ofonly a questionnaire is measured by the 19 20 8 volume under the surface (VUS), which is a multiclass generalization of AUC of a ROC between 21 22 9 the questionnaire score and the physician’s severity assessment17. 23 24 25 10 Other Clinical utilities 26 27 11 Convenience in clinical practice is measured by the average time taken to complete each 28 29 30 12 questionnaire or receive a diagnosis from a physician. 31 32 13 Clinical utility in monitoring treatment efficacy in patients is measured by assessing the correlation 33 34 35 14 with the SF-20 during follow-up visits. 36 37 15 Sample Size Calculation http://bmjopen.bmj.com/ 38 39 40 16 The sample size calculation considers the comparison of diagnostic accuracy for both SSD 41 42 17 identification and severity assessment, whichever is larger. In the pilot study, the prevalence of 43 44 18 SSD was 76.9% among patients who were referred to the special clinics (where physicians qualified 45 on September 25, 2021 by guest. Protected copyright. 46 47 19 as national psychological counsellors and psychologists practice medicine); the AUC of the ROC 48 49 20 for the PHQ-15 was 0.88; and the VUS of the multiclass ROC for the PHQ-15 with respect to the 50 51 21 severity assessment was 0.7. The correlation between the SSS-CN and PHQ-15 scores was 0.6. 52 53 22 With a non-inferiority margin of 0.05, α=0.025, and β=0.8, the sample size for SSD diagnosis was 54 55 56 23 852. With a non-inferiority margin of 0.1, α=0.025, and β=0.8, the sample size for severity 57 58 24 assessment was 517. Therefore, as the overall sample size of this study was N=852 with SSD- 59 60
12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 26 BMJ Open
1 2 3 1 positive N+=655 and SSD-negative N-=197, both the positive and negative sample size BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 requirements were met. 7 8 3 Statistical Analysis 9 10 11 4 We will report our results according to STARD. We will compute the median (P25, P75) scores 12 13 5 for each questionnaire and the number and percentage of patients (%) in each diagnostic category 14 15 6 as descriptive statistics. 16 17 18 7 Reliability will be measuredFor usingpeer Cronbach’s review α. The criterion only validity will be measured by the 19 20 8 kappa coefficient between the questionnaire score and the physician assessment. Construct validity 21 22 9 23 will be tested using confirmatory factor analyses. 24 25 10 The primary analysis of the diagnostic performance will consist of two comparisons using 26 27 11 Bonferroni’s correction: (1) the non-inferior comparison of the SSS-CN with the PHQ-15 with 28 29 30 12 respect to SSD diagnostic accuracy, as measured by the AUC of the ROC with =0.05, =0.025 31 32 13 in the whole study population using Delong’s method18; and (2) severity of PHQ-15 based on 33 34 14 scores (normal: 0–4; low: 5–9; medium: 10–14; high: 15–30). SSS-CN scores ranging from 20 to 35 36 37 15 29, 30 to 39, 40 to 59, and ≥60 correspond to normal, mild, moderate, and severe SSD, respectively. http://bmjopen.bmj.com/ 38 39 16 The non-inferior comparison will also be conducted between the SSS-Ch and the PHQ-15 with 40 41 17 respect to SSD severity, as measured by the VUS with =0.1, =0.025 in the population with a 42 43 17 44 18 confirmed SSD diagnosis using a Z-test . Both comparisons will use the physician’s diagnosis as 45 on September 25, 2021 by guest. Protected copyright. 46 19 the reference standard. If neither non-inferiority criterion is met, the corresponding superiority 47 48 20 will be tested. 49 50 51 21 As a secondary analysis, the sensitivity, specificity, and positive and negative predictive values will 52 53 22 also be determined. Prespecified cutoff values will be validated. In the follow-up data, 54 55 23 questionnaire scores by time will be demonstrated in a line chart with error bars. 56 57 58 59 60
13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 26
1 2 3 1 Missing values will be imputed with multiple imputation under the assumption of MAR17. BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 Subgroup analysis according to gender and age will also be conducted. All statistical analyses will 7 8 3 be performed with R (version 3.5.1) 9 10 4 Patient and Public Involvement Statement 11 12 13 5 Patients were involved at the design stage of the trial, including ensuring that the content of the 14 15 6 SSS-CN questionnaire can be understood and that the length of the consultation time, the 16 17 7 18 manner of notificationFor of the peerdisease condition, review the follow-up only method, and the dissemination of 19 20 8 the results are acceptable. Before the formal recruitment started, we received feedback from 21 22 9 patients who had SSD during a pretest of the case report form (CRF), and this feedback was 23 24 10 used to improve the final design of the CRF. We carefully assessed the burden of the trial 25 26 27 11 interventions on patients. We intend to disseminate the main results to the trial participants via 28 29 12 email. The study outcomes will be disseminated in conference reports and academic publications. 30 31 13 32 Ethics and Dissemination Ethical approval was obtained from the Renji Hospital Human 33 34 14 Research Ethics Committee, approval number 2015016. The findings of this study will be 35 36 15 disseminated via peer-reviewed journals and presented at international conferences. 37 http://bmjopen.bmj.com/ 38 39 16 Current Status 40 41 17 The first study participant was enrolled in November 2017. As of June 2019, patient recruitment 42 43 44 18 has not been completed. 45 on September 25, 2021 by guest. Protected copyright. 46 19 47 48 49 20 50 51 52 53 54 55 56 57 58 59 60
14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 26 BMJ Open
1 2 3 1 DISCUSSION BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 2 In this study protocol, we describe a diagnostic study design that evaluates the efficacy of a newly 7 8 3 developed somatic and psychological symptom scale adapted to China for patients with suspected 9 10 4 somatic diseases. This scale might be applied as a first-line instrument for screening and monitoring 11 12 13 5 treatment efficacy in individual outpatient consultations. We expect that physicians will benefit 14 15 6 from the SSS-CN on a clinically significant level in the form of improved self-confidence and 16 17 7 timeliness; participants will benefit from this scale in the form of improved awareness of the 18 For peer review only 19 8 disease and improved ability to self-monitor their symptoms. Moreover, we will compare the 20 21 22 9 characteristics of the SSS-CN with another somatic symptom questionnaire, namely, the PHQ15. 23 24 10 The SSS-CN is designed as a “one-stop shop” tool that combines somatic items with mental 25 26 27 11 disorder items. This design is consistent with the suggestion in the DSM-5 that somatic symptoms 28 29 12 are likely accompanied by depression and anxiety1. Somatic and mental symptoms may interact, 30 31 13 and mental symptoms may be triggered differently from conventional mental diseases among SSD 32 33 14 patients. Clinically, it is not easy to clearly separate the body from mental status, and the 34 35 36 15 significance of each item is unknown. We caution that 50% of mental items may increase the 37 http://bmjopen.bmj.com/ 38 16 incidence of SSD, and a subgroup score with only somatic symptom items is used for this appraisal. 39 40 17 41 In our study, there is no plan to supplement medication treatment of psychotherapy. This is 42 43 18 because there are societal and cultural culture differences in response to psychotherapy between 44 45 19
Asian and non-Asian patients. The Chinese World Mental Health Survey (2001–02) conducted in on September 25, 2021 by guest. Protected copyright. 46 47 20 Beijing and Shanghai found that only 3.4% of respondents with a psychiatric disorder sought 48 49 21 19 50 professional help during the previous 12 months . Similarly, in a large epidemiologic study 51 52 22 conducted in four provinces of China[63004 participants aged 18 years or older in 96 urban 53 54 23 neighbourhoods and 267 rural villages], only 8% of individuals with mental disorders sought 55 56 24 professional help within the general healthcare setting, and only 5% sought help from mental 57 58 25 20 59 health professionals (mainly hospital-based psychiatrists) . Second, Chinese and Asian Americans 60
15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 26
1 2 3 1 are likely to drop out and prematurely terminate psychotherapy services8. Third, there is a shortage BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 of psychiatrists, psychiatric nurses, and counselling and clinical psychologists to provide 7 21 8 3 psychotherapy . In particular, China had only 1.49 psychiatrists per 100 000 people, while, on 9 10 4 average, middle- and high-income countries worldwide have 2.03 psychiatrists per 100 000. Finally, 11 12 5 insurance currently pays for treatment with medication but typically does not support 13 14 6 15 psychotherapy, community recovery services, or preventive care. 16 17 7 The study has several strengths. First, we introduce a tool to facilitate daily clinical work. The tool 18 For peer review only 19 8 provides clinicians with an easy-to-use questionnaire for screening suspected SSD patients and 20 21 22 9 referring the patients to specific doctors. Second, our previous study showed the reliability and 23 24 10 factorial validity of the SSS-CN by utilizing an early version of it16. The current study further 25 26 11 modifies the SSS-CN based on the DSM-5 and, for the first time, evaluates its clinical utility. Third, 27 28 12 patients will benefit from the SSS-CN in the form of improved awareness of the disease and 29 30 31 13 improved ability to self-monitor their symptoms. 32 33 14 This trial has some limitations. First, SSD can be accompanied by diagnosed medical disorders. 34 35 36 15 The current study, however, represents the efficacy of the SSS-CN only in patients without 37 http://bmjopen.bmj.com/ 38 16 organic diseases. Therefore, further research on the application of SSS-CN in patients with both 39 40 17 SSD and diagnosed medical disorders is required. Moreover, the epidemiology of primary 41 42 18 healthcare facilities is different from the epidemiology of general hospitals; therefore, the 43 44 45 19 diagnostic accuracy in a health care sample requires additional investigation. Second, the study on September 25, 2021 by guest. Protected copyright. 46 47 20 was designed as a mid-term investigation with four measurement time points; thus, missing data 48 49 21 must be considered. Because only 16% of patients in the primary care evaluation of mental 50 51 22 disorders (PRIME-MD) study were involved in the follow-up22, we estimate that there will be a 52 53 54 23 high rate of missing data in our study. Because of the difficulty with compliance, only a small 55 56 24 fraction (approximately 16%) of patients in study would be involved in the follow-up, and the 57 58 25 result of monitoring the treatment effect may be affected by loss to follow-up. 59 60
16 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 26 BMJ Open
1 2 3 1 This study will help to clarify whether the SSS-CN is an effective tool for rapidly screening and BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 2 6 assessing the severity of symptoms in patients with suspected SSD in a general hospital clinic and 7 8 3 during follow-up. If the SSS-CN is found to be effective, it can be implemented as a first-line 9 10 4 screening and follow-up option. Additionally, we expect that the SSS-CN could provide 11 12 5 personalized information to consulting physicians in a timely manner. The study results will 13 14 6 15 contribute to better outpatient care for patients with SSD. 16 17 7 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
17 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 26
1 2 3 Acknowledgements: We thank all the patients who participated and advised us throughout the BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 study design and implementation for their contributions. 7 8 Conflict of interests: The authors declare that they have no competing interests. 9 10 Ethical approval: Ethical approval was provided by the Renji Hospital Human Research Ethics 11 12 Committee, approval number 2015016. 13 14 15 Consent for publication: All participants to date have provided written informed consent. 16 17 Authors' contributions: MJ: substantial contributions to the conception, design and 18 For peer review only 19 interpretation of data, drafting and critical revisions for important intellectual content. WTZ: 20 21 analysis, statistics and interpretation of data, drafting the manuscript. XS: design and 22 23 24 implementation of study, acquisition of data, analysis and interpretation of data, drafting the 25 26 manuscript. CG: analysis, statistics and interpretation of data. BXC: acquisition of data, analysis 27 28 and interpretation of data, drafting the manuscript. ZHF: acquisition of data, analysis and 29 30 interpretation of data, drafting the manuscript. JLM: substantial contributions to the conception, 31 32 33 design and interpretation of data, critical revisions for important intellectual content. JP: substantial 34 35 contributions to the conception, design and interpretation of data. 36 37
Funding: This work was supported by the National Natural Science Foundation of China http://bmjopen.bmj.com/ 38 39 (81470391 and 81470389); National Science Fund for Distinguished Young Scholars (81625002); 40 41 42 Shanghai ShenKang Hospital Development Center (16CR3020A and 16CR3034A); Shanghai 43 44 Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20172014 and 45 on September 25, 2021 by guest. Protected copyright. 46 20152209); Shanghai Outstanding Academic Leaders Program (18XD1402400); Shanghai Sailing 47 48 Program(17YF1410500); Shanghai Pudong Health Development Center (PW2018D-03); Shanghai 49 50 51 Jiao Tong University (YG2016QN78, YG2016MS45 and YG2015ZD04). 52 53 Registration name: The validation and utility of the Somatic Symptom Scale-China (SSS-CN) for 54 55 assessing somatic symptom disorder in general hospital outpatients. 56 57 58 59 60
18 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 26 BMJ Open
1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 1. Barsky AJ, Orav EJ, Bates DW. Somatization increases medical utilization and costs 7 independent of psychiatric and medical comorbidity. Archives of general psychiatry 8 2005;62(8):903-10. doi: 10.1001/archpsyc.62.8.903 9 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 10 11 Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Association Publishing 12 2013. 13 3. Barsky AJ. Assessing somatic symptoms in clinical practice. JAMA Intern Med 14 2014;174(3):407-8. doi: 10.1001/jamainternmed.2013.12177 15 4. Liang D, Mays VM, Hwang WC. Integrated mental health services in China: challenges 16 and planning for the future. Health Policy Plan 2018;33(1):107-22. doi: 17 10.1093/heapol/czx137 18 For peer review only 19 5. Jr SG. The course of somatization and its effects on utilization of health care resources. 20 Psychosomatics 1994;35(3):263. 21 6. Hahn SR, Kroenke K, Spitzer RL, et al. The difficult patient: prevalence, psychopathology, 22 and functional impairment. Journal of General Internal Medicine 1996;11(1):1. 23 7. Axelsson E, Andersson E, Ljotsson B, et al. The health preoccupation diagnostic interview: 24 inter-rater reliability of a structured interview for diagnostic assessment of DSM-5 25 26 somatic symptom disorder and illness anxiety disorder. Cogn Behav Ther 27 2016;45(4):259-69. doi: 10.1080/16506073.2016.1161663 28 8. Leong FT, Lau AS. Barriers to providing effective mental health services to Asian 29 Americans. Ment Health Serv Res 2001;3(4):201-14. 30 9. Gierk B, Kohlmann S, Kroenke K, et al. The somatic symptom scale-8 (SSS-8): a brief 31 measure of somatic symptom burden. JAMA Intern Med 2014;174(3):399-407. doi: 32 10.1001/jamainternmed.2013.12179 33 34 10. Gierk B, Kohlmann S, Toussaint A, et al. Assessing somatic symptom burden: a 35 psychometric comparison of the patient health questionnaire-15 (PHQ-15) and the 36 somatic symptom scale-8 (SSS-8). J Psychosom Res 2015;78(4):352-5. doi: 37
10.1016/j.jpsychores.2014.11.006 http://bmjopen.bmj.com/ 38 11. Tu CY, Liao SC, Liu CY, et al. Application of the Chinese Version of the Whiteley 39 Index-7 for Detecting DSM-5 Somatic Symptom and Related Disorders. 40 Psychosomatics 2016;57(3):283-91. doi: 10.1016/j.psym.2015.12.010 41 42 12. Toussaint A, Murray AM, Voigt K, et al. Development and Validation of the Somatic 43 Symptom Disorder-B Criteria Scale (SSD-12). Psychosom Med 2016;78(1):5-12. doi: 44 10.1097/PSY.0000000000000240 45
13. Toussaint A, Lowe B, Brahler E, et al. The Somatic Symptom Disorder - B Criteria Scale on September 25, 2021 by guest. Protected copyright. 46 (SSD-12): Factorial structure, validity and population-based norms. J Psychosom Res 47 2017;97:9-17. doi: 10.1016/j.jpsychores.2017.03.017 48 49 14. Laferton JAC, Stenzel NM, Rief W, et al. Screening for DSM-5 Somatic Symptom 50 Disorder: Diagnostic Accuracy of Self-Report Measures Within a Population Sample. 51 Psychosom Med 2017;79(9):974-81. doi: 10.1097/PSY.0000000000000530 52 15. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use: 53 Guideline on clinical evaluation of diagnostic agents. 54 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/ 55 09/WC500003584.pdf. 56 57 16. Qi Z, Jialiang M, Chunbo L, et al. Developing of somatic self-rating scale and its 58 reliability and validity. Chinese Journal of Behavioral Medicine and Brain Science 59 2010;19(9):847-9. 60
19 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 26
1 2 3 17. Nakas CT, Yiannoutsos CT. Ordered multiple-class ROC analysis with continuous BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 measurements. Stat Med 2004;23(22):3437-49. doi: 10.1002/sim.1917 5 6 18. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more 7 correlated receiver operating characteristic curves: a nonparametric approach. 8 Biometrics 1988;44(3):837-45. 9 19. Shen YC, Zhang MY, Huang YQ, et al. Twelve-month prevalence, severity, and unmet 10 need for treatment of mental disorders in metropolitan China. Psychol Med 11 2006;36(2):257-67. doi: 10.1017/S0033291705006367 12 20. Phillips MR, Zhang J, Shi Q, et al. Prevalence, treatment, and associated disability of 13 14 mental disorders in four provinces in China during 2001-05: an epidemiological 15 survey. Lancet 2009;373(9680):2041-53. doi: 10.1016/S0140-6736(09)60660-7 16 21. Liu C, Chen L, Xie B, et al. Number and characteristics of medical professionals working 17 in Chinese mental health facilities. Shanghai Arch Psychiatry 2013;25(5):277-85. doi: 18 10.3969/j.issn.1002-0829.2013.05.003For peer review only 19 22. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of 20 21 PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental 22 Disorders. Patient Health Questionnaire. Jama 1999;282(18):1737-44. 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
20 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 26 BMJ Open
1 2 3 Figure Legends BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from 4 5 6 Figure 1 The Somatic Symptom Scale-China (SSS-CN). 7 8 9 Figure 2 Study flow. SSS-CN, Somatic Symptom Scale-China; PHQ-15: Patient Health 10 11 Questionnaire-15; PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety 12 13 Disorder Scale-7; SF-20: 20-Item Short Form Health Survey; SSD: Somatic Symptom Disorder. 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 26 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 Figure 1 46 47 210x297mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 26 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 Figure 2 26 27 338x190mm (300 x 300 DPI) 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 26 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 Section & Topic No Item 2 TITLE OR ABSTRACT 3 Page 2, line 12-15 1 Identification as a study of diagnostic accuracy using at least one measure of accuracy 4 (such as sensitivity, specificity, predictive values, or AUC) 5 ABSTRACT 6 7 Page 2 2 Structured summary of study design, methods, results, and conclusions 8 (for specific guidance, see STARD for Abstracts) 9 INTRODUCTION 10 Page 4,line 2-page 5, line 21 3 Scientific and clinical background, including the intended use and clinical role of the index test 11 Page 5,line 22-Page 6,line7 4 Study objectives and hypotheses 12 METHODS 13 Study design 5 Whether data collection was planned before the index test and reference standard 14 Page 8,line 13-14,pros were performed (prospective study) or after (retrospective study) 15 Participants 6 Eligibility criteria 16 Page 9,line 10-14 For peer review only 17 18 Page 8,line 16-21 7 On what basis potentially eligible participants were identified 19 (such as symptoms, results from previous tests, inclusion in registry) 20 Page 8,line 21-22 8 Where and when potentially eligible participants were identified (setting, location and dates) 21 Page 8,line 16,consecutive 9 Whether participants formed a consecutive, random or convenience series 22 Test methods 10a Index test, in sufficient detail to allow replication 23 Page 7,line 11-Page 8,line 10 24 Page 9,line 20-Page 10,line7 10b Reference standard, in sufficient detail to allow replication 25 Page 9,line 21-24 11 Rationale for choosing the reference standard (if alternatives exist) 26 Page 8,line 7-10 12a Definition of and rationale for test positivity cut-offs or result 27 categories of the index test, distinguishing pre-specified from 28 Page 10, line1-3 12b Definitionexploratory of and rationale for test positivity cut-offs or result categories 29 of the reference standard, distinguishing pre-specified from exploratory 30 31 Page 8,line 25-Page 9,line1 13a Whether clinical information and reference standard results were available 32 to the performers/readers of the index test Page 9,line 1-3 13b Whether clinical information and index test results were available
33 http://bmjopen.bmj.com/ 34 to the assessors of the reference standard 35 Analysis 14 Methods for estimating or comparing measures of diagnostic accuracy 36 Page12，line 3-9 37 Page13, line 10-20 38 Page 10,line 6-7 15 How indeterminate index test or reference standard results were handled 39 Page 14,line 1 16 How missing data on the index test and reference standard were handled 40 Page14，line 2 17 Any analyses of variability in diagnostic accuracy, distinguishing pre-specified from exploratory
41 on September 25, 2021 by guest. Protected copyright. 42 Page 12,line 15-Page 13,line2 18 Intended sample size and how it was determined 43 RESULTS 44 Participants 19 Flow of participants, using a diagram 45 NA 20 Baseline demographic and clinical characteristics of participants 46 NA 21a Distribution of severity of disease in those with the target condition 47 NA 21b Distribution of alternative diagnoses in those without the target condition 48 NA 22 Time interval and any clinical interventions between index test and reference standard 49 Test results 23 Cross tabulation of the index test results (or their distribution) 50 by the results of the reference standard 51 NA 24 Estimates of diagnostic accuracy and their precision (such as 95% confidence intervals) 52 53 NA 25 Any adverse events from performing the index test or the reference standard 54 DISCUSSION 55 Page 16,line 15-Page 17,line 26 Study limitations, including sources of potential bias, statistical uncertainty, and generalisability 56 2 57 Page 17,line 3-8 27 Implications for practice, including the intended use and clinical role of the index test 58 59 OTHER INFORMATION 60 Page 2,line 23;Page 18,lastFor 2 peer28 reviewRegistration only - http://bmjopen.bmj.com/site/about/guidelines.xhtml number and name of registry lines Page 25 of 26 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
Page 7,line 5-7 29 Where the full study protocol can be accessed 1 Page 18 30 Sources of funding and other support; role of funders 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40
41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 26 BMJ Open: first published as 10.1136/bmjopen-2018-024290 on 26 September 2019. Downloaded from
1 STARD 2015 2 3 4 A I M 5 STARD stands for “Standards for Reporting Diagnostic accuracy studies”. This list of items was developed to contribute to the 6 completeness and transparency of reporting of diagnostic accuracy studies. Authors can use the list to write informative study 7 8 reports. Editors and peer-reviewers can use it to evaluate whether the information has been included in manuscripts 9 submitted for publication. 10 11 E X P L A N A T I O N 12 13 A diagnostic accuracy study evaluates the ability of one or more medical tests to correctly classify study participants as having a 14 target condition. This can be a disease, a disease stage, response or benefit from therapy, or an event or condition in the 15 future. A medical test can be an imaging procedure, a laboratory test, elements from history and physical examination, a 16 combination of these, or anyFor other method peer for collecting review information about the only current health status of a patient. 17 18 The test whose accuracy is evaluated is called index test. A study can evaluate the accuracy of one or more index tests. 19 20 Evaluating the ability of a medical test to correctly classify patients is typically done by comparing the distribution of the index 21 test results with those of the reference standard. The reference standard is the best available method for establishing the 22 presence or absence of the target condition. An accuracy study can rely on one or more reference standards. 23 24 If test results are categorized as either positive or negative, the cross tabulation of the index test results against those of the 25 reference standard can be used to estimate the sensitivity of the index test (the proportion of participants with the target 26 condition who have a positive index test), and its specificity (the proportion without the target condition who have a negative 27 index test). From this cross tabulation (sometimes referred to as the contingency or “2x2” table), several other accuracy 28 29 statistics can be estimated, such as the positive and negative predictive values of the test. Confidence intervals around 30 estimates of accuracy can then be calculated to quantify the statistical precision of the measurements. 31 32 If the index test results can take more than two values, categorization of test results as positive or negative requires a test
33 positivity cut-off. When multiple such cut-offs can be defined, authors can report a receiver operating characteristic (ROC) http://bmjopen.bmj.com/ 34 curve which graphically represents the combination of sensitivity and specificity for each possible test positivity cut -off. The 35 area under the ROC curve informs in a single numerical value about the overall diagnostic accuracy of the index test. 36 37 The intended use of a medical test can be diagnosis, screening, staging, monitoring, surveillance, prediction or prognosis. The 38 clinical role of a test explains its position relative to existing tests in the clinical pathway. A replacement test, for example, 39 40 replaces an existing test. A triage test is used before an existing test; an add-on test is used after an existing test.
41 on September 25, 2021 by guest. Protected copyright. 42 Besides diagnostic accuracy, several other outcomes and statistics may be relevant in the evaluation of medical tests. Medical 43 tests can also be used to classify patients for purposes other than diagnosis, such as staging or prognosis. The STARD list was 44 not explicitly developed for these other outcomes, statistics, and study types, although most STARD items would still apply. 45 46 47 D E V E L O P M E N T 48 This STARD list was released in 2015. The 30 items were identified by an international expert group of methodologists, 49 researchers, and editors. The guiding principle in the development of STARD was to select items that, when reported, would 50 51 help readers to judge the potential for bias in the study, to appraise the applicability of the study findings and the validity of 52 conclusions and recommendations. The list represents an update of the first version, which was published in 2003. 53 54 More information can be found on http://www.equator-network.org/reporting-guidelines/stard. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml