2024-16973. Supplemental Evidence and Data Request on Blood-Based Tests for Multiple Cancer Screening: A Systematic Review

PICOTS (Populations, Interventions, Comparators, Outcomes, Timing, and Setting)

[Detailed inclusion and exclusion criteria for systematic review on blood-based tests for multiple cancer screening]

Inclusion criteria	Exclusion criteria
Population
KQs 1, 2, 4, 5 Asymptomatic people 18 years of age or older KQ 3: People 18 years of age or older with either (1) biopsy-confirmed cancer or (2) who are asymptomatic without suspicion for cancer ( i.e., “healthy” individuals)	All KQ: People younger than 18 years of age; other than human populations ( e.g., animal or in vitro laboratory studies). KQs 1, 2, 4, 5: Adults with active cancer; adults undergoing evaluation for suspected cancer or cancer recurrence; adults with a history of invasive or hematologic cancer (other than nonmelanoma skin cancer) within the previous 3 years or a history of untreated cancer. KQ 3: Adults undergoing diagnostic evaluation for possible cancer or cancer recurrence.
Intervention
KQs 1, 2, 3, 4 • Blood tests used for the screening of at least 2 different types of cancer; tests using any analytes with any technology are eligible • Tests that were designed for cancer prognosis or surveillance in those with cancer or who have completed cancer treatment ( i.e., evaluation for minimal residual disease) are eligible as long as they are being evaluated in an eligible population as defined above • Blood tests used in combination with other tests such as imaging are eligible • MCSTs used instead of or in addition to usual care screening are eligible. We define usual care screening as follows: mammography (breast), direct visualization such as colonoscopy or stool-based tests (colorectal), low-dose computed tomography (lung), cytology, human papilloma virus testing (cervical), and prostate specific antigen (prostate) KQ 5: Tests or procedures (imaging, tissue biopsy, blood, urine, or cerebrospinal fluid) to evaluate positive signal(s) resulting from an MCST or procedures used to surveil patients who have a negative evaluation after a positive MCST signal	KQs 1, 2, 3, 4: Tests that are not blood based ( e.g., tissue, saliva, urine, or other bodily fluids). KQ 5: Tests or interventions not performed as a result of a positive MCST.
Comparator
KQs 1, 2, 4 • No screening test • Usual care cancer screening as defined above KQ 3: Tissue evaluation for confirmation of cancer; healthy asymptomatic status for controls KQ 5: No comparator required	KQs 1, 2, 4: No comparator group. KQ 3: No reference standard for comparison. KQ 5: Studies without a comparator group will not be excluded.
Outcomes
KQ 1: Cancer mortality overall and by cancer type, all-cause mortality, quality of life, functional status KQ 2a: Cumulative detection of cancer overall and by cancer type KQ 2b: Cumulative detection of late-stage cancer overall and by cancer type ( i.e., Stage III or IV or organ-specific definition of late stage); distribution of cancer stage at diagnosis ( i.e., stage shift) KQ 3: Accuracy (sensitivity, false negatives, specificity, false positives, predictive value) by cancer type and by cancer stage KQ 4: Psychosocial and emotional distress including anxiety and worry, false reassurance resulting in decrease in receipt of usual care screening or change in health behaviors associated with cancer (alcohol, tobacco, drug use, diet, physical activity), overdiagnosis, out-of-pocket patient costs, patient financial toxicity, and impact on insurability KQ 5: Radiation exposure from imaging, harms from invasive procedures, other adverse effects from evaluation that occur after a positive MCST, or out-of-pocket patient costs, patient financial toxicity, and impact on insurability	Outcomes not specifically indicated as included. Composite measures composed of both included and excluded outcomes will be included but considered only in sensitivity analyses.
Timing
KQ 1: At least 5 years of followup KQs 2, 4, 5: any timing KQ 3: At least 1 year of followup for prediagnostic performance designs.a For diagnostic performance designs, controls must be considered cancer free at the time of the sample	KQ 1: Studies with less than 5 years of followup.
Setting
• Recruitment from outpatient clinical settings, including primary care or specialty care, community-based or public health settings, electoral rolls, or other population-based registries • Countries with a United Nations Human Development Index of high or very high (Appendix A)	• Acute care settings, inpatient care settings. • Countries with a United Nations Human Development Index of less than high.
Study Design
KQs 1, 2, 4, 5: Randomized controlled trials; controlled trials KQs 1, 2: Registered NRSIs with 1 or more eligible benefit outcomes listed on study registration b KQs 4, 5: Unregistered NRSIs are also eligible KQ 3: Studies that provide data related to test accuracy; both prediagnostic test performance and diagnostic test performance designs are eligible. However, only diagnostic performance designs conducted in external validation cohorts are eligible. Further, if results for multiple variations of the test are reported by authors, only results from the test version selected for future commercial use or for evaluation in future intervention studies will be eligible	For all KQ: Modeling studies, case series, case reports, in vitro lab studies, studies designed to assess analytic validity, narrative reviews, systematic reviews (reviews will not be included but will be manually reviewed to identify primary research studies that the search may have missed). KQs 1, 2: Cohort studies that have not been registered or that report eligible outcomes that were not included in the study's registration b studies designed with a sample size that was not based on outcomes related to cancer detection or mortality. KQ 3: Accuracy results derived from discovery, development, internal validation, or split sample cohorts are not eligible because multiple analytes, technologies, or AI classifiers are being evaluated to develop the test and these results do not reflect the final state of the test that would be used in routine practice.
Language
English	Languages other than English.
a  KQ 3 prediagnostic accuracy performance studies that use disease-free longitudinal followup as a reference standard should have a minimum of 1-year followup.
b  Refers to study registration in ClinicalTrials.gov database, or another study registry such as those included in the World Health Organization International Clinical Trials Registry Platform.
KQ = key question; MCST = multiple cancer screening test; NRSI = non-randomized study of interventions.