Here is the design of a clinical trial:

Official Title: Screening Test Accuracy of a Gynocular™, HR-HPV Testing, and VIA for Detection of Cervical Intraepithelial Neoplasia, Grade Two and Above, in Women Living With HIV in Lusaka, Zambia

Included conditions:
- Uterine Cervical Neoplasms
- HIV/AIDS

Study Armgroups:
- {'label': 'Portable magnification device (Gynocular™)', 'description': "The Gynocular™ examination will be performed following the steps involved in colposcopy as described in the IARC colposcopy manual. These steps include: visualization of the vagina, vulva and cervix following insertion of a speculum, magnified assessment after application of normal saline, examination of cervical vessel patterns using the red-free mode (or green filter), application of 5% acetic acid for 1 minute and finally assessment following application with Lugol's iodine. The findings of the live examination will be documented using the parameters of the Swede score. Each parameter is scored between zero and two. Treatment will be based on the results found at histopathology, unless the woman is also VIA positive in which case, after biopsy she will undergo routine treatment as per local guidelines. The results will be used to determine the optimal threshold for treatment in WLHIV.", 'interventionNames': ['Diagnostic Test: Screening for CIN2+/HSIL']}
- {'label': 'Testing for high risk HPV (HRHPV)', 'description': "To reduce the number of examinations undergone by the study participant during the same day, HRHPV testing will be carried out at the time of the first gynecological examination by the VIA nurse (see next arm). Using specific single-use cervical cytobrush provided by GeneXpert, a specimen will be collected immediately prior to VIA examination. Cervical cytobrush specimens will be placed into ThinPrep PreservCyt (Cepheid, Sunnyvale, CA) immediately after collection. The HR-HPV testing of cervical specimens will be conducted by a GeneXpert™ machine (Cepheid, Sunnyvale, CA), which will be placed at the health facility and will be operated by a trained nurse in accordance with the manufacturer's instructions. Additionally, as part of the baseline clinical characteristics of the study participant, the study participant will undergo an STI test at the same time. The sample will be collected and tested using the same GeneXpertTM platform.", 'interventionNames': ['Diagnostic Test: Screening for CIN2+/HSIL']}
- {'label': 'Visual inspection with acetic acid (VIA)', 'description': 'VIA, which is standard of care for cervical cancer screening in Zambia, will be carried out using the methodology described by IARC. This is summarized as follows: visualization of the vagina, vulva and cervix following insertion of a speculum; assessment with the naked eye after application of normal saline; and further assessment after application of 5% acetic acid for 1 minute. This will be recorded as normal or abnormal by the assessor.', 'interventionNames': ['Diagnostic Test: Screening for CIN2+/HSIL']}
- {'label': 'Histopathological examination of tissue biopsies', 'description': 'All acetowhite lesions will be biopsied. When no lesion is seen, one biopsy is taken from each quadrant at the squamocolumnar junction. Biopsies will be sent and examined in a South African based lab. All histological slides will also be verified independently by an IARC trained pathologist at the end of the study. Histological endpoints are defined by the CIN classification system: CIN 1 affects only the lower third of the epithelium (mild dysplasia), CIN 2 involves two thirds of the epithelium and CIN 3 involves the full thickness (severe dysplasia and carcinoma in situ). These findings can be dichotomized by the Lower Anogenital Squamous Terminology into low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). All patients with CIN grade 2 that stained diffusely positive for p16 are considered as HSIL, all patients with CIN 3 are considered as HSIL. Expression of p16 will be visually assessed by immunohistochemistry.', 'interventionNames': ['Diagnostic Test: Screening for CIN2+/HSIL']}

Interventions:
- {'type': 'DIAGNOSTIC_TEST', 'name': 'Screening for CIN2+/HSIL', 'description': 'The investigators will compare three different screening methods: visual assessment with portable magnification device , visual inspection after application of acetic acid, screening for high risk variants of HPV. All patients will receive cervical biopsies and histopathological examination.', 'armGroupLabels': ['Histopathological examination of tissue biopsies', 'Portable magnification device (Gynocular™)', 'Testing for high risk HPV (HRHPV)', 'Visual inspection with acetic acid (VIA)']}

Primary Outcomes:
- {'measure': 'Test accuracy (sensitivity, specificity) of the Gynocular™ when used as stand-alone tests to detect CIN2+', 'description': 'To estimate the sensitivity and specificity of the Gynocular when used as a standalone tests to detect CIN2+ among WLHIV.', 'timeFrame': '6 months'}
- {'measure': 'Test accuracy (sensitivity, specificity) of HR-HPV when used as stand-alone tests to detect CIN2+', 'description': 'To estimate the sensitivity and specificity of HR-HPV when used as a standalone tests to detect CIN2+ among WLHIV.', 'timeFrame': '6 months'}
- {'measure': 'Test accuracy (sensitivity, specificity) of VIA when used as stand-alone tests to detect CIN2+', 'description': 'To estimate the sensitivity and specificity of VIA when used as a standalone tests to detect CIN2+ among WLHIV.', 'timeFrame': '6 months'}

Please estimate the sample size based on the assumption: 
Screening accuracy measures will be estimated with 95% Wilson confidence intervals. There is an expected 10% loss to follow-up and up to 10% of tests that are not analysable or interpretable.
Sample size calculation and analysis
        This screening test accuracy study requires 350 participants to estimate the sensitivity and specificity of Gynocular, HR-HPV and VIA for CIN2+ lesions with the precision detailed in table 1. Screening accuracy measures will be estimated with 95% Wilson confidence intervals with no formal hypothesis testing between modalities.
        
          Table 1
          
            Sensitivity and specificity table, n = 350. The expected 95% Wilson confidence interval for sensitivity and specificity with varying prevalence
          
          
            
              
                
                Expected 95% CIs for sensitivity (%)Expected 95% CIs for specificity (%)
              
              
                50
                55
                60
                65
                70
                75
                80
                85
                90
                95
              
            
            
              
                Expected prevalence (%)
                14
                37.5 to 64.4
                41.3 to 68.1
                45.2 to 71.8
                51.3 to 77.1
                55.5 to 80.5
                61.9 to 85.4
                66.4 to 88.5
                73.3 to 92.9
                78.2 to 95.6
                86.3 to 98.9
              
              
                
                  44.6 to 55.8
                
                
                  49.5 to 60.7
                
                
                  54.5 to 65.5
                
                
                  59.6 to 70.3
                
                
                  64.7 to 75.0
                
                
                  69.9 to 79.6
                
                
                  75.2 to 84.2
                
                
                  80.6 to 88.6
                
                
                  86.1 to 92.9
                
                
                  91.9 to 97.0
                
              
              
                16
                37.3 to 62.7
                42.4 to 67.6
                47.6 to 72.4
                51.2 to 75.5
                56.7 to 80.1
                62.3 to 84.5
                68.2 to 88.7
                74.3 to 92.6
                78.5 to 95.0
                85.4 to 98.2
              
              
                
                  44.3 to 55.7
                
                
                  49.4 to 60.7
                
                
                  54.2 to 65.3
                
                
                  59.4 to 70.2
                
                
                  64.6 to 75.0
                
                
                  69.9 to 79.8
                
                
                  75.0 to 84.1
                
                
                  80.5 to 88.7
                
                
                  86.2 to 93.0
                
                
                  91.8 to 96.9
                
              
              
                18
                38.8 to 62.7
                43.3 to 67.2
                48.0 to 71.5
                52.8 to 75.7
                57.6 to 79.8
                62.7 to 83.7
                67.8 to 87.5
                75.0 to 92.3
                80.7 to 95.6
                86.9 to 98.4
              
              
                
                  44.4 to 55.9
                
                
                  49.3 to 60.7
                
                
                  54.2 to 65.4
                
                
                  59.5 to 70.4
                
                
                  64.5 to 75.0
                
                
                  69.6 to 79.6
                
                
                  75.1 to 84.3
                
                
                  80.4 to 88.7
                
                
                  85.9 to 92.9
                
                
                  92.0 to 97.1
                
              
              
                20
                38.6 to 61.4
                44.1 to 66.8
                48.3 to 70.7
                54.0 to 75.8
                58.5 to 79.5
                64.5 to 84.2
                69.2 to 87.7
                75.7 to 92.1
                80.8 to 95.1
                88.1 to 98.5
              
              
                
                  44.2 to 55.8
                
                
                  49.1 to 60.7
                
                
                  54.2 to 65.6
                
                
                  59.2 to 70.3
                
                
                  64.4 to 75.1
                
                
                  69.6 to 79.7
                
                
                  74.9 to 84.3
                
                
                  80.3 to 88.7
                
                
                  85.9 to 93.0
                
                
                  91.8 to 97.0
                
              
              
                22
                39.7 to 61.5
                43.5 to 65.2
                48.6 to 70.0
                53.8 to 74.7
                59.2 to 79.2
                64.6 to 83.6
                70.3 to 87.8
                74.7 to 90.9
                80.8 to 94.6
                87.4 to 98.0
              
              
                
                  44.3 to 56.1
                
                
                  49.0 to 60.7
                
                
                  54.2 to 65.7
                
                
                  59.0 to 70.3
                
                
                  64.3 to 75.1
                
                
                  69.6 to 79.8
                
                
                  74.7 to 84.2
                
                
                  80.3 to 88.7
                
                
                  86.0 to 93.1
                
                
                  91.6 to 96.9
                
              
            
          
          
            
              %, percentage; CI, Confidence interval; n, number of women.
            
          
        
        We will enrol 450 women to obtain data from at least 350 patients for statistical analyses. We expect the prevalence of CIN2+ in WLHIV in Zambia to be 16%â20%.8 27 28 We expect disease prevalence to be lower than in previous years. Increases in the number of women receiving ART, and commencing treatment at higher CD4 cell counts,29 may lead to a decline in HPV prevalence.30 Higher rates of voluntary male circumcision in male partners may also contribute to lower levels of HPV infection.30 We also estimate that there might be up to 10% loss to follow-up and up to 10% of tests that are not analysable or interpretable. We have implemented rigorous data collection methods to avoid missing data, such as patient demographics, clinical history and test results.
        A complete list of outcomes can be found in our clinical trials registration and in the online supplemental material 1.
        
          10.1136/bmjopen-2020-037955.supp1
          Supplementary data
          
            
          
        
        Primary outcomes are:
        
          
            The sensitivity and specificity of the Gynocular, HR-HPV and VIA when used as stand-alone tests to detect CIN2+ among WLHIV.
          
        
        Secondary outcomes are:
        
          
            Other test accuracy measures of the Gynocular, HR-HPV testing and VIA which include positive and negative predictive values, positive and negative likelihood ratios, false-positive rate, false-negative rate, number needed to screen, and area under the receiver operating characteristic (ROC) curve and the diagnostic ORs.
          
          
            Estimates of accuracy for tests when they are done in sequence. For example, HR-HPV positive test followed by Gynocular, and HR-HPV positive test followed by VIA.
          
          
            Estimates of test accuracy in subgroups defined by age, menopausal status, parity, education, ART status, CD4 cell count, HIV RNA viral load, coinfection with T. vaginalis, methods of contraception, and earlier treatment for precancer and potential effect modification. The specific categorisation of the variables in the subgroup analysis is defined in the online supplemental material 2.
          
          
            Area under the ROC curve for the Swede score determined by Gynocular.
          
        
        
          10.1136/bmjopen-2020-037955.supp2
          Supplementary data
          
            
          
        
        A detailed statistical analysis plan has been drafted as a separate document, to describe planned analyses for the predefined outcomes and planned subgroup analyses. This can be found as an attachment to our clinical trials registration. In summary, two-by-two tables will be created to calculate sensitivity and specificity, positive and negative predictive values, positive and negative likelihood ratios, false-positive rate, false-negative rate, diagnostic odds ratio, and number needed to screen. Test accuracies will be calculated for each test in a stand-alone and add-on capacity, with corresponding confidence intervals using the Wilson score method.31 Area under the ROC curve for the Swede score as determined by the Gynocular will also be calculated. We will also evaluate test accuracy in subgroups defined by age, menopausal status, parity, education, ART status, CD4 cell count, HIV RNA viral load, coinfection with T. vaginalis, methods of contraception and earlier treatment for precancer. We will use logistic regression models to assess whether these patient characteristics have an influence on the association between each diagnostic test and disease status.
        Indeterminate results from the index test or reference standard will be reported, and sensitivity analysis will be performed to quantify the possible range of accuracy if participants with an indeterminate test or reference standard data are classified as positive or negative. The distribution of baseline characteristics between the participants with missing data and those without will be compared and managed similarly, with a sensitivity analysis to quantify the possible range of accuracy if participants with missing data are classified as diseased or non-diseased. If the missing data can be categorised as missing at random, such as lost samples, technical failures or accidental deviations from the protocol, multiple imputation may be used to reconstruct the data.