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Background: Timing of initiation of screening for breast cancer is controversial in the United States.Objective: To determine the threshold relative risk (RR) at which the harm-benefit ratio of screening women aged 40 to 49 years equals that of biennial screening for women aged 50 to 74 years.Design: Comparative modeling study.Data Sources: Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and medical literature.Target Population: A contemporary cohort of women eligible for routine screening.Time Horizon: Lifetime.Perspective: Societal.Intervention: Mammography screening starting at age 40 versus 50 years with different screening methods (film, digital) and screening intervals (annual, biennial).Outcome Measures: Benefits: life-years gained, breast cancer deaths averted; harms: false-positive mammography findings; harm-benefit ratios: false-positive findings/life-years gained, false-positive findings/deaths averted.Results Of Base-case Analysis: Screening average-risk women aged 50 to 74 years biennially yields the same false-positive findings/life-years gained as biennial screening with digital mammography starting at age 40 years for women with a 2-fold increased risk above average (median threshold RR, 1.9 [range across models, 1.5 to 4.4]). The threshold RRs are higher for annual screening with digital mammography (median, 4.3 [range, 3.3 to 10]) and when false-positive findings/deaths averted is used as an outcome measure instead of false-positive findings/life-years gained. The harm-benefit ratio for film mammography is more favorable than for digital mammography because film has a lower false-positive rate.Results Of Sensitivity Analysis: The threshold RRs changed slightly when a more comprehensive measure of harm was used and were relatively insensitive to lower adherence assumptions.Limitation: Risk was assumed to influence onset of disease without influencing screening performance.Conclusion: Women aged 40 to 49 years with a 2-fold increased risk have similar harm-benefit ratios for biennial screening mammography as average-risk women aged 50 to 74 years. Threshold RRs required for favorable harm-benefit ratios vary by screening method, interval, and outcome measure.Primary Funding Source: National Cancer Institute. [ABSTRACT FROM AUTHOR]