Tables 2, ,3,3, ,4,4, and and55 show the PICOTS elements for KQs 1, 2, 4, and 5. These are described in detail in Supplementary File 3. Given that we will not undertake de novo synthesis for KQ 3, we have not included PICOTS elements for this KQ.

Eligibility criteria for key question 2 (comparative diagnostic accuracy)

Individuals with a cervix, 15 years of age and older, who have been sexually active, and who have no symptoms of cervical cancera

Population subgroups:

– By age group (15–19, 20–24, 25–29, 30–69, 70+)

– HPV-vaccinated populations

– Primary high-risk HPV testing with HPV nucleic acid testsb alone

– High-risk HPV testing with HPV nucleic acid tests, followed by some form of triage (e.g. cytology or HPV testing with partial genotyping for HPV 16 or 18, sequential partial genotyping for HPV 16 or 18 followed by cytology to further triage those positive for HPV 16 or 18).

Subgroups:

– Method of sample collection for high-risk HPV testing (i.e. self-collected (home vs. in clinic) vs. clinician-collected)

– Type of assay (i.e. generic, partial genotyping, full genotyping)

– HPV test threshold for a positive result (i.e. 1 pg/mL, 2 pg/mL)

HPV test using in situ hybridization, p16 immunostaining, or HPV viral load

Earlier versions of commercial tests that have been replaced (e.g. Hybrid Capture 1)

Urine for sample collection

Point-of-care tests

– Conventional or liquid-based cytology, with or without follow-up by high-risk HPV testing

– High-risk HPV testing with HPV nucleic acid tests, followed by different forms of triage than in the index test

– hrHPV testing with HPV nucleic acid tests, using a different method of sample collection (i.e. self-sampled (home vs. clinic) vs. clinician-sampled)

• Colposcopy with histologic examination of tissue specimens, when indicated.

• Study protocol stipulates that reference standard is applied to:

– All patients, or

– All screening test-positive patients and a subset (e.g. random 10%) of screening test-negative patients

Diagnostic test accuracy:

Number and proportion of people positive and negative on each test (TP, FP, TN, FN), sensitivity and specificity to screen for high-grade cervical lesions (CIN 2, CIN 3, HSIL), and/or invasive cervical cancer (squamous cell carcinoma or adenocarcinoma)

– Observational studies (e.g. prospective or retrospective cohorts, or cross-sectional studies) in which all participants receive both the index and comparator screening test, followed by verification of disease status using the reference standard in all patients or in all screening test-positive patients and a subset (e.g. random 10%) of screening test-negative patients

– Randomized controlled trials where participants are randomized to different screening tests but all receive the same reference standard

AGC atypical glandular cells, AIS adenocarcinoma in situ, CIN cervical intraepithelial neoplasia, FN false negative, FP false positive, HPV human papillomavirus, HSIL high-grade squamous intraepithelial lesions, TN true negative, TP true positive

aWe will include studies where up to 25% of the participants had a recent abnormal screening result

bEligible HPV tests include generic assays, as well as partial and full genotyping assays able to detect at least some high-risk HPV genotypes (e.g. HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) and available commercially in Canada or reasonably perceived to potentially be available in Canada. Examples of eligible high-risk HPV tests include the Cobas 4800 HPV Amplification/Detection Kit (Roche Molecular Systems, Inc.), Linear Array HPV Genotyping Test (Roche), Aptima HPV assay (Hologic, Inc.), Aptima HPV 16 18/45 Genotype Assay (Hologic), Cervista HPV HR assay (Hologic), Abbott RealTime High-Risk HPV (Abbott Molecular), Digene DML-2000 HPV Test Hybrid Capture 2 (Qiagen Sciences LLC), and Xpert HPV test (Cepheid)

Eligibility criteria for key question 4 (patient values and preferences)

Individuals with a cervix, or who have had their cervix removed as part of treatment for cervical cancer, 15 years of age and older (patients and the general public)

Population subgroups:

– Age (15–19, 20–24, 25–29, 30–69, 70+)

– Risk groups: immunocompromised (e.g. HIV, organ transplantation, chemotherapy or chronic use of corticosteroids, use of disease-modifying anti-rheumatic drugs or biologics), risk behaviours (e.g. early sexual debut, women who have sex with women, individuals who have multiple sexual partners, smoking), Indigenous peoples, rural populations, immigrants, lower SES, pregnant individuals, HPV-vaccinated populations

– Previous screening history (regular as per guidance vs. not regular (under) vs. never-screened)

– Experience with critical outcome(s) related to screening or,

– Exposure to clinical scenarios or information about potential critical outcomes and/or estimates of effect on outcome risks from screening, or

– No experience or exposure to information about outcomes, but authors are soliciting probability trade-offs or ratings of different potential critical outcomes (e.g. number of biopsies acceptable to prevent one early diagnosis of invasive cervical cancer)

– Focus of study is on consideration of possible, or assessment of experienced, outcomes from screening.

Exposure moderators: differing descriptions or experience of outcomes in terms of stage, treatments received, severity, time since diagnosis (immediate vs. first year vs. later years); number of outcomes considered; differing estimates of magnitudes of effect from screening (if applicable)

Apart from studies with direct (e.g. time-trade off) or indirect (e.g. based on EQ-5D) measurement of heath state utilities, participants need to consider at least one outcome that may be a harm from screening (e.g. false positives, overdiagnosis [e.g. hrHPV+ but never will get cancer], increased CIN 2+ detection).

Focus on the harms from management of lesions or cancer.

– Different critical outcome or groups of outcomes (e.g. critical benefits vs. harms)

– Healthy state without outcome (for utility studies)

– No comparison (for utility studies)

– No or another intervention, if applicable for interpreting outcome importance, i.e. no screening, another screening strategy (e.g. having different magnitude of effects), no information (e.g. in studies using decision aids).

When only one arm (e.g. receiving decision aid) of a comparative study is used for interpreting data on patient preferences, the study will be classified as a non-comparative study.

a) Utility values/weights for the potential outcomes from screening

b) Non-utility, quantitative information about relative importance of different outcomes (e.g. rating scales using ordinal or interval variables, ranking; preference for or against screening [screening attendance, intentions, or acceptance] or preferred screening strategy based on different outcome risk descriptions, strength of associations about outcome ratings with screening behaviours or intentions)

c) Qualitative information indicating relative importance between outcomes

d) Rank-order of importance of outcomes, based on data from a) to c) above, as applicable.

Data must relate to the outcomes considered critical to the Task Force. Outcome groupings a) to c) above will be included in a hierarchical manner for each critical screening outcome.

Any quantitative or qualitative study design using the methods described below:

– Utility values/weights measured directly using time trade-offa, standard gambleb, visual analogue scales, conjoint analysis with choice experiments or probability trade-offs

– Utility values/weights measured or estimated indirectly, e.g. from transforming several health state domains from multi-attribute utility indexes such as EQ-5D to utilities using general population preferences, including mapping from generic or disease-specific health-related quality of life instruments

– Non-utility, quantitative information about relative importance of different outcomes, e.g. rating scales using ordinal or interval variables, ranking; preference for or against screening (screening attendance, intentions, or acceptance) or preferred screening strategy based on different outcome risk descriptions, strength of associations about outcome ratings with screening behaviours or intentions)

– Qualitative information indicating relative importance between benefits and harms

– Rank-order of importance of outcomes

HPV human papillomavirus

aTime trade-off measures the value placed on attributes of a commodity by requiring individuals to choose between different scenarios, where in each scenario, the commodity in question has varying levels of different attributes

bStandard gamble approaches require that respondents choose between a lifetime in a certain health state or a gamble between different health states, whereas time trade-off requires respondents to choose between living for a period in less than perfect health, as opposed to a shorter period in perfect health

Eligibility criteria for key question 5 (interventions to increase screening rates)

Individuals with a cervix who would meet the criteria for cervical cancer screening, but who have never been screened or who have been under-screened, as defined by the study authors, when assessed against current screening recommendations (e.g. for screening interval).

Population subgroups:

– Indigenous peoples

– Immigrant groups

– Rural populations

– Low socioeconomic status populations

Individuals with symptoms of cervical cancer or previous abnormal test results on cervical screening (unless cleared to return to normal screening)

Individuals who have had complete surgical removal of the cervix

– Mail-out or opt-in (invitation to request) self-sampling for hrHPV screening

– Other interventions aimed at individuals or primary care providers with the intent to increase acceptability of screening (e.g. screening reminders, education, counselling, provider recommendation, addressing cultural practices and beliefs, patient-provider communication)

– No intervention

– Routine care (could include reminders or invitations to screen, or other forms of minimal intervention like pamphlets, posters)

– Primary care settings or settings available through primary care referral (note we will not exclude primary care interventions that are implemented alongside or in support of broader public health initiatives (e.g. reminders))

– Studies involving populations from Very High Development Index countries

– Randomized controlled trials

– Non-randomized trials and cohort studies (will only be considered if there are no data available from randomized controlled trials)

HPV human papillomavirus

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