{
  "abstract": "Abstract Objective To investigate the accuracy of risk prediction models and scores for diagnosing ovarian cancer in premenopausal women presenting to secondary care with symptoms and abnormal test results.Design Prospective cohort study.Setting Secondary care in 23 hospitals in the UK between June 2015 and March 2023.Participants Premenopausal women presenting with non-specific symptoms, and raised serum levels of cancer antigen 125 or abnormal imaging results, were prospectively recruited, predominantly referred through the NHS urgent suspected cancer pathway from primary care. A head-to-head comparison of the accuracy of the six risk prediction models and scores was conducted using donated blood and ultrasound scans performed by NHS staff trained in the use of International Ovarian Tumour Analysis (IOTA) imaging terminology. The index tests used were Risk of Malignancy Index 1 (with pre-stated thresholds of 200, 250), Risk of Malignancy Algorithm (7.4%, 11.4%, 12.5%, 13.1%), IOTA Assessment of Different Neoplasias in the adnEXa (ADNEX) (3%, 10%), IOTA simple rules risk model (3%, 10%), IOTA simple rules, and cancer antigen 125 (CA 125, 87 IU/mL). Participants were classified as having primary invasive ovarian cancer versus having benign or normal pathology according to the reference standard determined from surgical specimens or biopsies by histology or cytology, if undertaken, or else at 12 month follow-up. After June 2018, because of covid restrictions and concerns about sample size, recruitment was restricted to only women undergoing surgery within three months of presentation to clinic (in whom ovarian cancer was more likely).Main outcome measures Diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data.Results 88 of 1211 premenopausal women received diagnoses of primary ovarian cancer: 49 of 857 women in the pre-June 2018 cohort (prevalence of 5.7%) and 39 of 354 women in the post-June 2018 cohort (11.0%). For the diagnosis of primary ovarian cancer (n=799 women, after exclusion of 58 other diagnoses), Risk of Malignancy Index 1 at the 250 threshold had a sensitivity of 42.6% (95% confidence interval (CI) 28.3 to 57.8; specificity 96.5%, 94.7 to 97.8). Compared with Risk of Malignancy Index 1 at the 250 threshold, CA 125 and all other tests had higher sensitivity (CA 125 at 87 IU/mL threshold: 55.1%, 40.2 to 69.3, P=0.06; Risk of Malignancy Algorithm at 11.4% threshold: 79.2%, 65.0 to 89.5, P<0.001; IOTA ADNEX at 10% threshold: 89.1%, 76.4 to 96.4, P<0.001; IOTA simple rules risk at 10% threshold: 83.0%, 69.2 to 92.4, P<0.001; IOTA simple rules: 75.0%, 56.6 to 88.5, P=0.01) and lower specificity (CA 125 at 87 IU/mL threshold: 89.0%, 86.5 to 91.2, P<0.001; Risk of Malignancy Algorithm at 11.4% threshold: 73.1%, 69.6 to 76.3, P<0.001; IOTA ADNEX at 10% threshold: 75.1%, 71.4 to 78.6, P<0.001; IOTA simple rules risk at 10% threshold: 76.0%, 72.4 to 79.3, P<0.001; IOTA simple rules: 95.2%, 93.0 to 96.9, P=0.06). Results for IOTA simple rules were inconclusive in 120 of 799 participants. Analysis of the complete cohort (n=1211), including the 354 premenopausal women with a higher likelihood of developing ovarian cancer, yielded similar results.Conclusions Compared to Risk of Malignancy Index 1 at 250 threshold—the test currently used in NHS secondary care to triage women to tertiary care—most tests improve sensitivity but reduce specificity. Ultrasound triage with the IOTA ADNEX model at 10% in secondary care demonstrated the highest sensitivity gain, with a comparable decline in specificity to other comparator tests. Ultrasound with the IOTA ADNEX model at 10% should be considered the new standard of care test for triaging premenopausal women in secondary care. Implementation should incorporate staff training and quality assurance.Trial registration ISRCTN17160843.",
  "authors": [
    {
      "affiliations": [
        "PanBirmingham Gynaecological Cancer Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham B71 4HJ, UK",
        "Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham B71 4HJ, UK"
      ],
      "name": "Sudha Sundar"
    },
    {
      "affiliations": [
        "Department of Applied Health Science, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK"
      ],
      "name": "Ridhi Agarwal"
    },
    {
      "affiliations": [
        "Department of Applied Health Science, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK"
      ],
      "name": "Katie Scandrett"
    },
    {
      "affiliations": [
        "Department of Applied Health Science, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK"
      ],
      "name": "Clare Davenport"
    },
    {
      "affiliations": [
        "Department of Development and Regeneration, KU Leuven, Leuven, Belgium",
        "Leuven Unit for Health Technology Assessment Research (LUHTAR), KU Leuven, Leuven, Belgium"
      ],
      "name": "Ben Van Calster"
    },
    {
      "affiliations": [
        "Southampton University Hospitals, NHS Trust, Southampton, UK"
      ],
      "name": "Susanne Johnson"
    },
    {
      "affiliations": [
        "Durham and Darlington NHS Trust, Darlington, UK"
      ],
      "name": "Partha Sengupta"
    },
    {
      "affiliations": [
        "West Hertfordshire Hospitals NHS Trust, Watford, UK"
      ],
      "name": "Radhika Selvi-Vikram"
    },
    {
      "affiliations": [
        "PanBirmingham Gynaecological Cancer Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham B71 4HJ, UK",
        "Department of Applied Health Science, University of Birmingham, Birmingham, UK"
      ],
      "name": "Fong Lien Kwong"
    },
    {
      "affiliations": [
        "Centre for Medical Imaging, University College London, London, UK"
      ],
      "name": "Sue Mallett"
    },
    {
      "affiliations": [
        "University of Nottingham, Nottingham, UK"
      ],
      "name": "Caroline Rick"
    },
    {
      "affiliations": [
        "St Peter's College, University of Oxford, Oxford, UK"
      ],
      "name": "Sean Kehoe"
    },
    {
      "affiliations": [
        "Department of Development and Regeneration, KU Leuven, Leuven, Belgium",
        "Department of Obstetrics and Gynaecology, University Hospitals KU Leuven, Leuven, Belgium"
      ],
      "name": "Dirk Timmerman"
    },
    {
      "affiliations": [
        "Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK"
      ],
      "name": "Tom Bourne"
    },
    {
      "affiliations": [
        "Patient Representative, Birmingham, UK"
      ],
      "name": "Hilary Stobart"
    },
    {
      "affiliations": [
        "University of Exeter Medical School, University of Exeter, Exeter, UK"
      ],
      "name": "Richard D Neal"
    },
    {
      "affiliations": [
        "Department of Women’s Cancer, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, UK"
      ],
      "name": "Usha Menon"
    },
    {
      "affiliations": [
        "Department of Women’s Cancer, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, UK",
        "MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK"
      ],
      "name": "Aleksandra Gentry-Maharaj"
    },
    {
      "affiliations": [
        "Birmingham Clinical Trials Unit, University of Birmingham, UK"
      ],
      "name": "Lauren Sturdy"
    },
    {
      "affiliations": [
        "Birmingham Clinical Trials Unit, University of Birmingham, UK"
      ],
      "name": "Ryan Ottridge"
    },
    {
      "affiliations": [
        "Department of Applied Health Science, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK"
      ],
      "name": "Jonathan J Deeks"
    },
    {
      "affiliations": [],
      "name": "on behalf of the ROCkeTS collaborators"
    }
  ],
  "title": "Diagnostic tests for ovarian cancer in premenopausal women with non-specific symptoms (ROCkeTS): prospective, multicentre, cohort study",
  "uid": "b43e4aa5-e054-5e17-bcdf-13bd4e386f52"
}