Cost-effectiveness of Screening BRCA1/2 Mutation Carriers With Breast Magnetic Resonance Imaging | Breast Cancer | JAMA | JAMA Network
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Figure 1. Sensitivity Analysis for the Cost-Effectiveness of Adding Annual MRI Screening in BRCA1/2 Mutation Carriers Aged 35 to 54 Years
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*See Table 2.
†Cost-effectiveness of adding MRI to mammographic screening from the ages of 35 to 54 years is evaluated relative to mammographic screening alone. MRI indicates magnetic resonance imaging; QALY, quality-adjusted life-year.

Figure 2. Incremental QALYs vs Costs of Adding Annual MRI Screening in BRCA1/2 Mutation Carriers as Risk Varies
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MRI indicates magnetic resonance imaging; QALY, quality-adjusted life-year. The origin represents mammographic screening alone for individuals aged 25 to 69 years. All other points include MRI screening at specified ages. Axes refer to change in cost and QALYs relative to mammographic screening alone. The cost-effectiveness ratio for comparing one screening strategy with another is the reciprocal of the slope of the line between the points corresponding to each strategy.

Table 1. Patient, Tumor, and Screening Test Characteristics
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Table 2. Resource Utilization Prompted by Screening BRCA1/2 Mutation Carriers
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Table 3. Costs Due to Breast Cancer Screening, Diagnosis, and Treatment
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Table 4. Health State Utilities
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Table 5. Effectiveness of Screening BRCA1/2 Mutation Carriers Aged 25 to 69 Years
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Table 6. Effectiveness and Cost-effectiveness of Alternative Screening Strategies in BRCA1 and BRCA2 Mutation Carriers
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Table 7. Cost-effectiveness of Annual MRI Screening When Utility for BRCA1/2 Mutation Carriage Varies
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Table 8. Cost-effectiveness of MRI Screening When MRI Screening Frequency Varies
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Original Contribution
May 24/31, 2006

Cost-effectiveness of Screening BRCA1/2 Mutation Carriers With Breast Magnetic Resonance Imaging

Author Affiliations

Author Affiliations: Departments of Radiology (Drs Plevritis, Sigal, Daniel, and Ikeda) and Medicine (Drs Kurian and Stockdale), Division of Oncology, Center for Primary Care and Outcomes Research, Stanford University School of Medicine, Stanford, Calif; and VA Palo Alto Health Care System, Palo Alto, Calif (Dr Garber).

JAMA. 2006;295(20):2374-2384. doi:10.1001/jama.295.20.2374

Context Women with inherited BRCA1/2 mutations are at high risk for breast cancer, which mammography often misses. Screening with contrast-enhanced breast magnetic resonance imaging (MRI) detects cancer earlier but increases costs and results in more false-positive scans.

Objective To evaluate the cost-effectiveness of screening BRCA1/2 mutation carriers with mammography plus breast MRI compared with mammography alone.

Design, Setting, and Patients A computer model that simulates the life histories of individual BRCA1/2 mutation carriers, incorporating the effects of mammographic and MRI screening was used. The accuracy of mammography and breast MRI was estimated from published data in high-risk women. Breast cancer survival in the absence of screening was based on the Surveillance, Epidemiology and End Results database of breast cancer patients diagnosed in the prescreening period (1975-1981), adjusted for the current use of adjuvant therapy. Utilization rates and costs of diagnostic and treatment interventions were based on a combination of published literature and Medicare payments for 2005.

Main Outcome Measures The survival benefit, incremental costs, and cost-effectiveness of MRI screening strategies, which varied by ages of starting and stopping MRI screening, were computed separately for BRCA1 and BRCA2 mutation carriers.

Results Screening strategies that incorporate annual MRI as well as annual mammography have a cost per quality-adjusted life-year (QALY) gained ranging from less than $45 000 to more than $700 000, depending on the ages selected for MRI screening and the specific BRCA mutation. Relative to screening with mammography alone, the cost per QALY gained by adding MRI from ages 35 to 54 years is $55 420 for BRCA1 mutation carriers, $130 695 for BRCA2 mutation carriers, and $98 454 for BRCA2 mutation carriers who have mammographically dense breasts.

Conclusions Breast MRI screening is more cost-effective for BRCA1 than BRCA2 mutation carriers. The cost-effectiveness of adding MRI to mammography varies greatly by age.

Women who inherit deleterious mutations in the BRCA1 or BRCA2 cancer susceptibility genes have a 45% to 65% lifetime risk of developing breast cancer.1 The risk can be reduced by prophylactic mastectomy but many BRCA1/2 mutation carriers decline prophylactic mastectomy2 and seek effective screening strategies that detect breast cancer early. Current screening guidelines recommend annual mammography starting at age 25 years3 despite the low sensitivity of mammography in this population.4-6 Screening with contrast-enhanced breast magnetic resonance imaging (MRI) has been shown to detect disease earlier than mammography in high-risk women; cancers detected by MRI are often axillary lymph-node negative and stage I.6-14 Recently, the Blue Cross and Blue Shield Technology Evaluation Center reported that screening with breast MRI provides clinical benefit to high-risk women.15 Although breast MRI screening is highly sensitive, it increases the rate of false-positive test results, and it has not been shown to reduce breast cancer mortality.16 Furthermore, breast MRI screening is at least 10 times more expensive than mammographic screening and generates higher diagnostic costs.7,9,14 Because cost may be the greatest barrier to broader evaluation and dissemination of breast MRI screening, its cost-effectiveness is a critical consideration.

We evaluated the cost-effectiveness of adding breast MRI screening in BRCA1/2 mutation carriers, incorporating the known associated health benefits and costs, and projecting long-term effects through computer simulation modeling. A randomized clinical trial would provide the best evidence for any breast cancer mortality reduction attributable to MRI screening but no such trial is under way. Even if a randomized clinical trial were initiated today, mortality outcomes would not be available for at least 15 years. Moreover, accumulating evidence for improved breast cancer detection with MRI screening has led some to question the ethics of randomizing BRCA1/2 mutation carriers to mammographic screening alone.6-14 Our model-based analysis uses the best evidence available today to establish the cost-effectiveness of adding breast MRI screening in BRCA1/2 mutation carriers and identifies key factors that influence it.


A continuous-time Monte Carlo simulation model was developed in C++ to estimate the health and economic outcomes of BRCA1/2 mutation carriers under protocols of no screening, annual mammography from ages 25 to 69 years, and annual mammography from ages 25 to 69 years plus annual MRI for specific age groups. Health benefits, measured in terms of life-years and quality-adjusted life-years (QALYs), and total health-related costs for each screening protocol were computed separately for BRCA1 and BRCA2 mutation carriers. The cost-effectiveness ratio of screening was computed as the cost per QALY gained by screening and evaluated from a societal perspective per the guidelines of the Panel on Cost-Effectiveness of Health and Medicine.17

Overview of Computer Simulation Model

A continuous-time Monte Carlo simulation model was developed to estimate the impact of breast cancer screening and treatment on the clinical and economic outcomes of individual breast cancer patients. The model has been used to quantify the effects of screening mammography and adjuvant therapy on breast cancer mortality trends in the general US population from 1975 to 2001.18,19 It was modified to characterize BRCA1/2 mutation carriers, to include the tumor detection characteristics of mammography and MRI in this population, and to incorporate costs. Assumptions about the natural history of breast cancer and the performance of the screening tests are the main determinants of any survival benefit derived from screening in this model. Model inputs are presented in Table 1, Table 2, Table 3, and Table 4.

Patient Characteristics

A simulated cohort of female 25-year-old BRCA1/2 mutation carriers, born in 1980, was followed over their lifetimes starting in 2005. These women had no prior breast cancer history and had not undergone prophylactic mastectomy or chemoprevention (Table 1). The effect of a background rate of prophylactic bilateral salpingo-oophorectomy (BSO) was assumed to be incorporated into baseline breast cancer incidence rates.1 Women who had ovarian cancer treated with BSO before menopause were assigned a subsequent 50% reduction in breast cancer risk.47 Breast cancer survival for the BRCA1/2 mutation carriers was estimated using the methods described below. Age-specific ovarian cancer survival for the BRCA1/2 mutation carriers was assumed to be similar to that for the general population captured in the US Surveillance, Epidemiology and End Results (SEER) database; the effect of better ovarian cancer survival, as reported in BRCA1/2 mutation carriers, was examined in a sensitivity analysis.48-51 Mortality from causes other than breast and ovarian cancer was assumed to be equivalent to all-cause mortality of the general population.52

Natural History Model of Breast Cancer

Screening-related outcomes were modeled by mathematically superimposing screening events onto the natural history of the disease.18 A previously developed53 mathematical model of the natural history of invasive breast cancer was adapted for this analysis. The distributions for the detected tumor size and stage in BRCA1/2 mutation carriers who are not undergoing screening were derived using SEER data on breast cancer patients diagnosed in the prescreening period (1975-1981), stratified by age and tumor grade.54 Ductal carcinoma in situ was embedded in the prognostically similar category of localized invasive breast cancer smaller than 1 cm. The mean tumor volume doubling time of invasive breast cancer was estimated by calibrating our model to the reported sensitivity of annual breast MRI screening in the high-risk population.7,9,14 In our model, high-grade tumors grow faster and consequently are more likely to be missed by screening than low-grade tumors. The model inputs that characterize the population and the natural history of breast cancer are summarized in Table 1.

Detection Characteristics of MRI and Mammography

A tumor size-dependent threshold mechanism was used for tumor detection by MRI and mammography.18 It was assumed that all tumors larger than 5 mm are detectable by MRI. In previous work, we estimated a median mammographic detection size of 1 cm for tumors that are mammographically visible18; we assumed that an age-dependent proportion of tumors are not visible on mammography unless larger than 5 cm (Table 1).7,9,14

The simulation model produces estimates of screening sensitivity, specificity, lead time, and overdiagnosis rates. To estimate the number of patients with false-positive findings, the number of screen-detected cancer patients was subtracted from the total number of patients undergoing screen-prompted diagnostic procedures. The results are reported in terms of specificity.

Treatment and Breast Cancer Survival

It was assumed that 50% of women older than 50 years and 40% of women younger than 50 years elect bilateral mastectomy with breast reconstruction when diagnosed with unilateral breast cancer and that the remainder are treated with unilateral mastectomy with breast reconstruction.28-30 In the absence of screening and adjuvant therapy, breast cancer survival for BRCA1/2 mutation carriers was assumed to be equivalent to breast cancer survival for breast cancer patients in the SEER database predating the widespread use of mammography and adjuvant therapy, stratified by age, tumor size, stage, and grade at detection. In the presence of screening and adjuvant therapy, these SEER-derived survival curves were modified according to the mode of detection and type of adjuvant therapy received (Table 1).18,19 In our model, all breast cancer patients receive adjuvant chemotherapy with an anthracycline- and taxane-based combination26,27; all patients with estrogen receptor–positive disease also receive adjuvant tamoxifen.42


Resource utilization rates and costs of MRI and mammography are listed in Table 2 and Table 3. Probabilities of diagnostic procedures prompted by screening were obtained from prior publications (Table 2).7,14,31 Costs of screening and related procedures were based on Medicare reimbursement for 2005 (Table 3)33; breast MRI costs are about 10 times as much as mammography. Costs of cancer therapy were obtained from prior literature.37-39 Costs of screening and treatment included costs of time lost from work (Table 3).34,36,41,43 All costs were updated to 2005 US dollars. Cost-effectiveness ratios incorporated 3% annual discounting of costs and QALYs.17


We used published adjustments for quality of life associated with aging and breast and ovarian cancer measured in patients with BRCA1/2 mutations whenever available and otherwise in the general population (Table 4).45,46,55

Sensitivity Analyses

We performed 1-way and multi-way sensitivity analyses by varying key model parameters within the ranges specified in Table 1, Table 2, Table 3, and Table 4.

Effectiveness and Cost-effectiveness of Adding Annual MRI Screening From Ages 25-69 Years

Nondiscounted health benefits of screening BRCA1/2 mutation carriers from ages 25 to 69 years with annual mammography alone and with MRI added to annual mammography are presented in Table 5. For BRCA1 mutation carriers, adding MRI increases the sensitivity of annual screening from 35% to 85%, the proportion of axillary lymph-node negative cancers from 57% to 81%, the mean lead time from approximately 1.5 to 3 years, and the false-positive rate from approximately 5% to 25%; overdiagnosis of invasive cancer is negligible. Outcomes for BRCA2 mutation carriers are similar. With MRI, life expectancy increases from 71.2 to 73.3 years for BRCA1 mutation carriers and from 78.2 to 79.6 years for BRCA2 mutation carriers. For both BRCA1 and BRCA2 mutation carriers, adding MRI reduces breast cancer mortality by 23% over that obtained from mammography alone. Relative to annual screening with mammography alone, the cost of adding annual MRI from the ages of 25 to 69 years is $88 651 per QALY gained for BRCA1 mutation carriers and $188 034 per QALY gained for BRCA2 mutation carriers, assuming a 3% discount rate.

Cost-effectiveness of Adding Annual MRI Screening at Different Ages

We evaluated alternative annual screening strategies whereby all women were screened with mammography from ages 25 to 69 years and screened with MRI from the ages of 25 to 69 years, 25 to 64 years, 25 to 59 years, 25 to 54 years, 25 to 49 years, 30 to 69 years, 30 to 64 years, 30 to 59 years, 30 to 54 years, 30 to 49 years, 35 to 69 years, 35 to 64 years, 35 to 59 years, 35 to 54 years, 35 to 49 years, 40 to 69 years, 40 to 64 years, 40 to 59 years, 40 to 54 years, and 40 to 49 years. The alternative strategies are listed in Table 6 in order of increasing cost per QALY gained, along with their respective sensitivities and specificities. The strategies that produce inferior outcomes at greater costs were omitted or were eliminated by extended dominance.17 The screening strategy with the lowest cost per QALY gained, other than mammography alone, adds annual MRI for 10 years from ages 40 to 49 years at a cost per QALY gained of $43 484 for BRCA1 mutation carriers and $111 600 for BRCA2 mutation carriers. The strategy with the next lowest cost per QALY gained adds annual MRI for 15 years from ages 35 to 49 years for BRCA1 mutation carriers and from ages 40 to 54 years for BRCA2 mutation carriers. The optimal 15-year age range differs for BRCA1 and BRCA2 mutation carriers because of differences in age-specific breast cancer incidence by mutation status. After the strategy of adding annual MRI for 15 years, the strategy with the next lowest cost per QALY gained adds annual MRI for 20 years from ages 35 to 54 years in BRCA1 and BRCA2 mutation carriers.

Sensitivity Analysis of Annual MRI Screening for Ages 35 to 54 Years

Relative to screening with mammography alone, the cost per QALY gained by adding MRI from ages 35 to 54 years is $55 420 for BRCA1 mutation carriers and $130 695 for BRCA2 mutation carriers. One-way sensitivity analyses of modeling assumptions on these cost-effectiveness ratios appear in Figure 1 and Table 7. Magnetic resonance imaging becomes more cost-effective as breast cancer risk increases and less cost-effective as the risk decreases. Because the cost-effectiveness of MRI screening is evaluated relative to mammographic screening, it is highly sensitive to the performance of mammography. As the performance of mammography decreases, MRI screening becomes more cost-effective. For women younger than 50 years with extremely dense breasts on mammography, adding MRI costs $41 183 per QALY gained for BRCA1 mutation carriers and $98 454 per QALY gained for BRCA2 mutation carriers. The cost-effectiveness of MRI is affected little by plausible variations in mean tumor volume doubling time, ovarian cancer survival, and the detection threshold of MRI.

The cost-effectiveness of MRI is sensitive to both the cost of MRI and the discount rate, relative to no screening. The cost per QALY gained using an MRI-based screening strategy for BRCA1 and BRCA2 mutation carriers declines roughly in proportion to reductions in the cost of MRI. Discounting has a large effect on the cost-effectiveness ratio; it affects life-years significantly more than costs because the benefits of MRI are delayed whereas screening costs are immediate. Varying the probability of screen-prompted diagnostic testing has less influence. In a multi-way sensitivity analysis, the utilities of carrying a BRCA1 or BRCA2 mutation with screening outcomes were varied.If the reassurance of a negative MRI yields a greater gain in quality of life than would a negative mammogram because MRI has higher sensitivity, then the cost-effectiveness of MRI significantly improves, particularly among BRCA2 mutation carriers (Table 7).

Alternative MRI Frequencies for Ages 35 to 54 Years

The cost-effectiveness of screening BRCA1/2 mutation carriers from the ages of 35 to 54 years with annual mammography plus MRI was evaluated at different frequencies (semiannual, annual, and biennial). It was assumed that women are recalled more often for additional diagnostic testing when screened less frequently and recalled less often when screened more frequently. Semiannual MRI costs more than $150 000 per QALY gained for both BRCA1 and BRCA2 mutation carriers but annual MRI in BRCA1 mutation carriers and biennial MRI in BRCA2 mutation carriers each cost less than $100 000 per QALY gained (Table 8).

Annual MRI Screening for Ages 35 to 54 Years Without Mammography

When mammography was omitted, we found that annual MRI among women aged 35 to 54 years costs $37 713 per QALY gained for BRCA1 mutation carriers and $80 058 per QALY gained for BRCA2 mutation carriers. These results likely underestimate the cost per QALY gained by MRI screening because we did not model the possibility that some breast cancers may be detectable by mammography only.

Annual MRI Screening Strategies for Different Breast Cancer Risk

Because variation in breast cancer risk had the largest effect on the cost-effectiveness of screening, annual MRI screening was evaluated at different starting and stopping ages for 3 different levels of cumulative breast cancer risk. Potentially cost-effective strategies in order of increasing cost per QALY gained appear in Figure 2. If the cumulative breast cancer risk by age 70 years is 85% for both BRCA1 and BRCA2 mutation carriers, annual MRI screening strategies that cost less than $50 000 per QALY gained can be identified in both groups; at a cost-effectiveness threshold of $100 000 per QALY gained, annual MRI screening from ages 30 to 64 years is cost-effective in both groups. At a 25% cumulative risk by age 70 years, no annual MRI screening strategy costs less than $150 000 per QALY gained in BRCA2 mutation carriers.


Screening BRCA1 and BRCA2 mutation carriers for breast cancer with MRI added to mammography can be cost-effective at selected ages even though MRI is expensive and increases the number of false-positive findings. At a cost-effectiveness threshold of $100 000 per QALY gained, adding annual MRI from the ages of 35 to 54 years is cost-effective among all BRCA1 mutation carriers and among BRCA2 mutation carriers for whom mammography is insensitive. Magnetic resonance imaging has a larger role in screening BRCA1 mutation carriers because they are at greater risk for developing breast cancer and their cancers are more aggressive than those that develop in BRCA2 mutation carriers.

Even among BRCA1 mutation carriers, annual MRI screening is not cost-effective among younger women (aged 25-34 years) because of their lower breast cancer incidence, and among older women (aged ≥55 years) because of declining quality of life and competing risk of death from other causes. Screening with MRI becomes more cost-effective as the risk of breast cancer increases, mammography performance worsens, greater quality of life gains accrue from MRI, and the cost of MRI decreases. Because of these factors, it may become cost-effective to screen women at younger and older ages under such conditions. Varying the frequency of MRI screening examinations may also make MRI more cost-effective at younger and older ages, but this possibility was not fully evaluated because there is no published data on MRI screening intervals other than 1 year. An exploratory analysis comparing different MRI screening frequencies for women aged 35 to 54 years demonstrated that annual MRI screening remains cost-effective for BRCA1 mutation carriers and biennial MRI screening becomes cost-effective for BRCA2 mutation carriers based on a cost-effectiveness threshold of $100 000 per QALY.

The cost-effectiveness of MRI screening depends critically on the accuracy of both MRI and mammography. The less accurately mammography performs relative to MRI, the more cost-effective MRI becomes. Per published data, we assigned a low sensitivity of mammography for women younger than 50 years and assumed it increased somewhat for women aged 50 years or older. Because most screening studies in BRCA1/2 mutation carriers have focused on women younger than 50 years,9,57 it is not known whether mammography has higher sensitivity in BRCA1/2 mutation carriers after menopause, as in the general population.58

Our analysis reveals an age-dependence on the cost-effectiveness of MRI that is partly attributable to the age-specific performance of mammography. In the future, the adoption of digital mammography and other improvements in mammography may alter the value of adding MRI screening.59 For example, a recent study reported that digital mammography is more sensitive than film-based mammography in premenopausal women and those with dense breasts.59 The cost-effectiveness of MRI screening can change in 2 ways if it is added to digital rather than conventional mammography. A more sensitive mammogram will prevent more breast cancer deaths, reducing the gains from adding MRI. However, if digital mammography is more expensive or results in more false-positive results, the incremental cost of MRI will be reduced. Depending on which of these 2 effects predominates, MRI screening may appear either more or less cost-effective when added to digital mammography.

Interventions that reduce breast cancer risk, such as BSO and chemoprevention, will make MRI less cost-effective. For example, if prophylactic BSO is more prevalent among premenopausal BRCA1/2 mutation carriers than we implicitly assumed, subsequent breast cancer risk will be lower and MRI screening will yield a smaller gain.3,60 The gain from MRI screening would be greater for BRCA1/2 mutation carriers who do not undergo premenopausal BSO. Similarly, if chemoprevention with prophylactic tamoxifen or other agents, which was not included in this analysis, should prove effective and widely accepted among BRCA1/2 mutation carriers,24,61,62 then screening would be less cost-effective. Changes in breast cancer treatment can also alter the cost-effectiveness of MRI screening. The use of breast conserving therapy, which was not included in this analysis, appears to be effective for BRCA1/2 mutation carriers30,63 and may become more prevalent with MRI screening because MRI detects smaller tumors. Breast conserving therapy may result in higher recurrence rates of local recurrence or new primary breast cancers than other surgical approaches, increasing the value of a sensitive test like breast MRI for surveillance. However, the impact of breast conserving therapy on the cost-effectiveness of breast MRI for screening is uncertain because the effect of this therapy on longevity, quality of life, and costs among BRCA1/2 mutation carriers is not known. Finally, if MRI detects cancers so early that chemotherapy can be reduced, then MRI screening will be more cost-effective.

Gaps in available data are responsible for several limitations of our model. Ductal carcinoma in situ was not included as a separate disease state in our model because little is known about its incidence and progression in BRCA1/2 mutation carriers and the ability of MRI to detect it.64 Screening with either mammography or MRI may lead to detection of ductal carcinoma in situ that would never threaten a woman's survival; this phenomenon is referred to as overdiagnosis. If mammography is more likely than MRI to overdiagnose ductal carcinoma in situ, MRI will be more cost-effective than reported herein, and the converse is also true. Finally, the effects of breast cancer screening, diagnosis, treatment, and survivorship on quality of life among BRCA1/2 mutation carriers have not been well studied but have a large influence on the cost-effectiveness of screening. For example, the increased sensitivity of MRI over mammography may enable more women to defer or avoid prophylactic mastectomy; this may apply especially to BRCA2 mutation carriers because their predicted breast cancer risk is lower compared with that of BRCA1 mutation carriers. However, the benefits of such an outcome will depend on the utility associated with mastectomy, which is likely to vary greatly across women.

Despite these uncertainties, our analysis shows that breast MRI screening is likely to be cost-effective in selected ages of women who carry genetic mutations that place them at high risk for developing breast cancer. Compared with the cost-effectiveness ratio of conventional mammography for women aged 40 to 49 years3,65 with average risk, adding annual MRI to screening mammography yields a lower cost-effectiveness ratio for BRCA1 mutation carriers aged 35 to 54 years and a comparable cost-effectiveness ratio for BRCA2 mutation carriers aged 35 to 54 years for whom conventional mammography is insensitive due to breast density. With substantial declines in its cost, breast MRI screening is likely to represent an acceptable value for a broader group of women.

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Article Information

Corresponding Author: Sylvia K. Plevritis, PhD, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 (

Author Contributions: Dr Plevritis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Plevritis, Garber.

Acquisition of data: Plevritis, Kurian, Ikeda, Stockdale.

Analysis and interpretation of data: Plevritis, Kurian, Sigal, Daniel, Garber.

Drafting of the manuscript: Plevritis, Kurian.

Critical revision of the manuscript for important intellectual content: Plevritis, Kurian, Sigal, Daniel, Ikeda, Stockdale, Garber.

Statistical analysis: Plevritis, Sigal, Garber.

Obtained funding: Plevritis.

Administrative, technical, or material support: Plevritis.

Study supervision: Plevritis.

Financial Disclosures: None reported.

Funding/Support: This study was funded by National Institutes of Health grants R01 CA829040, U01 CA088248, R01 CA66785 and by the California Breast Cancer Research Program Fellowship Award No. 11FB-0051.

Role of the Sponsors: None of the funders had any role in the conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

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