Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review

Purpose Polygenic risk influences susceptibility to cancer. We assessed whether polygenic risk scores could be used in conjunction with other predictors of future disease status in costeffective risk-stratified screening for cancer. Methods We undertook a systematic review of papers that evaluated the cost-effectiveness of screening interventions informed by polygenic risk scores compared with more conventional screening modalities. We included papers reporting cost-effectiveness outcomes with no restriction on type of cancer or form of polygenic risk modeled. We evaluated studies using the Quality of Health Economic Studies checklist. Results A total of 10 studies were included in the review, which investigated 3 cancers: prostate (n = 5), colorectal (n = 3), and breast (n = 2). Of the 10 papers, 9 scored highly (score >75 on a 0-100 scale) when assessed using the quality checklist. Of the 10 studies, 8 concluded that polygenic risk-informed cancer screening was likely to be more cost-effective than alternatives. Conclusion Despite the positive conclusions of the included studies, it is unclear if polygenic risk stratification will contribute to cost-effective cancer screening given the absence of robust evidence on the costs of polygenic risk stratification, the effects of differential ancestry, potential downstream economic sequalae, and how large volumes of polygenic risk data would be collected and used.


Section and Topic
Item # Checklist item Location where item is reported Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
Page 10 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Page 10 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 10 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If metaanalysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Page 10 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).
Page 10 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 10 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

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Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 10

RESULTS
Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Page 10-12 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

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Study characteristics 17 Cite each included study and present its characteristics. Page 12-13 Risk of bias in studies 18 Present assessments of risk of bias for each included study. Page 18-19 and Appendix 4 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.

Appendix 3
Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. Page 17-18 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered.
Page 2 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Page 2 24c Describe and explain any amendments to information provided at registration or in the protocol. N/A Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.

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Competing interests 26 Declare any competing interests of review authors. Page 24 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.

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Appendix 2 -Inclusion and exclusion criteria