Abstract
Keywords
Introduction
The COVID-19 pandemic has had an unprecedented impact on the healthcare system. In most jurisdictions, changes in clinical protocols and patient workflows were implemented to help protect patients and healthcare staff from possible exposure to COVID-19 and ensure care could be provided to those who were affected by COVID-19. These changes included omissions or interruptions in cancer diagnostic and screening tests; the resultant delays in diagnosis could lead to the upstaging of cancer and worse survival.
In the central Canadian province of Manitoba, on March 24, 2020, all nonessential diagnostic testing was postponed while urgent tests that were needed for immediate care continued to be provided. Cancer screening was also reduced or suspended until June 2020, which postponed follow-up diagnostic tests for individuals with a positive breast, colorectal (CRC), or cervical screening test. To better understand the impact of the COVID-19 pandemic on diagnostic tests for cancer, we examined the association between COVID-19 and the rate of bilateral and unilateral mammograms, breast ultrasounds, colposcopies, and colonoscopies in Manitoba, Canada from January 2015 until August 2022.
Materials and Methods
Manitoba is located in central Canada and has a population of approximately 1.39 million. 1 Two-thirds of the population lives in the capital city of Winnipeg. The province is divided into 5 Regional Health Authorities (RHAs). 2 CancerCare Manitoba (CCMB) is the provincial cancer agency responsible for providing clinical services to all Manitobans diagnosed with cancer. Manitoba has 3 publicly funded, population-based, organized cancer screening programs for breast (bilateral mammogram, 50-74 years of age), cervical (Pap test, 21-74 years of age), and colorectal (guaiac-based Hemoccult Sensa, 50-74 years of age) cancer operated by CCMB.
The first COVID-19 case in Manitoba was identified on March 12, 2020. By the end of March 2020, the provincial government declared a public health emergency and implemented restrictions to mitigate the impact of the virus. The peak of the first wave occurred in late March/early April 2020, the second at the end of November 2020, and the third in mid-May 2021. By the end of August 2021, approximately 78% of Manitobans had received 2 doses of the COVID-19 vaccine. 3 The peak of the 4th wave occurred in October 2021, the 5th in January 2022, and the 6th in April 2022. 4
Most individuals with an abnormal screening mammogram are referred for a diagnostic mammogram or a breast ultrasound. Breast imaging may also be ordered to assess symptomatic breast concerns, for surveillance after breast cancer treatment, and for screening high-risk women who are outside the screening program's target age range. Colposcopies are used for follow-up after high-grade or repeat low-grade abnormal Pap test results as well as for post-treatment surveillance. Colonoscopies are recommended after an abnormal fecal test, to assess symptoms, as routine screening for individuals at high risk for colorectal cancer, and as ongoing surveillance. Colonoscopies are scheduled through central intake offices in 2 RHAs (the Winnipeg RHA (WRHA) and the Southern Health—Santé Sud Regional Health Authority) and individual hospital-based endoscopy units by healthcare providers in all other RHAs. A small proportion of colonoscopies (approximately 20% of those in Winnipeg) are performed at 3 independent ambulatory endoscopy centers in Winnipeg which do not participate in the WRHA's central intake process. Referral reason for colonoscopies coordinated by the WRHA's central intake offices is categorized as elective, semiurgent, or urgent (Appendix A in the supplement lists referral reason details).
We used a population-based quasi-experimental cross-sectional study design to examine the rate of diagnostic tests for breast, CRC, and cervical cancer in Manitoba over time, before (January 1, 2015 until February 28, 2020) and after the start of the COVID-19 pandemic and the interventions that were implemented to mitigate its impact (April 1, 2020 until August 31, 2022). The colonoscopy rate by referral reason included only colonoscopies scheduled through the WRHA's Central Intake Office (for individuals who resided in Winnipeg and several communities adjacent to the city) from January 1, 2018 (start date for the full-fledged functioning of the WRHA Central Intake office) to December 31, 2022.
Data from Manitoba Health's Medical Services/Medical Claims database were used to determine bilateral and unilateral mammograms, breast ultrasounds, colposcopies, and colonoscopies. The accuracy and completeness of Manitoba Health's administrative data has been previously established.5–7 Data from the WRHA's Central Intake Office were used to determine the colonoscopy referral reason.
Outcomes included the rate per 100 000 by month for bilateral mammograms, unilateral mammograms, breast ultrasounds, colposcopies, and colonoscopies. Because of the impact of the pandemic on cancer screening found in prior analyses, 8 we examined rates for individuals <50, 50 to 74 (i.e., eligible for screening programs), and ≥75 years of age. Quarterly rates from January 1, 2015 to June 20, 2022 were used when examining rates by age group because of smaller counts. We also examined colonoscopy rates by sex (female, male) and for Winnipeg, by referral type (elective, semiurgent, urgent). We estimated the cumulative difference and percent cumulative difference between the fitted and counterfactual number of diagnostic tests as of August 31, 2022. The estimated cumulative difference in diagnostic tests was defined as the difference between the cumulative counterfactual count (the estimated number of tests in the absence of COVID-19) and the cumulative fitted count (i.e., smoothed estimates derived from observed data). The estimated percent cumulative difference in the number of diagnostic tests was defined as the cumulative difference in the fitted count divided by the cumulative difference in the counterfactual count. We also estimated the cumulative difference and percent cumulative difference between the fitted and predicted number of colonoscopies by referral status as of December 31, 2022 and determined the mean number of days from the referral date (i.e., the date of referral on the endoscopy referral form) to colonoscopy date by referral type. Sensitivity analyses were conducted by examining the quantiles of 0.50 (median) and 0.90.
We used an interrupted time series analysis which, unlike pre–post study designs, takes into consideration the baseline rate of events. 9 We compared post-COVID-19 (April 2020 onward) diagnostic test rates to counterfactual rates as if the pandemic had not occurred based on pre-COVID-19 trends (baseline trend). Linear and generalized linear models (i.e., Poisson, negative binomial (NB1 and NB2), gamma, inverse Gaussian, generalized Poisson, and Tweedie) were used to analyze diagnostic test counts. Scaled quantile residual plots were used to evaluate model fit. 10 Each model included a binary intervention term equal to 0 during the pre-COVID-19 period and 1 during the COVID-19 period and a time term defined as the number of months or quarters since the start of the study period. Fitted values (i.e., smoothed estimates of observed values) were generated using the observed values in the data frame. Counterfactual values were generated by predicting values with the binary indicator of the pandemic as 0 rather than 1. Nonlinear time effects (if present) were accounted for in the regression model using a flexible spline function. 11 To account for potential autocorrelation, a seasonality term was assessed for inclusion in the model with residuals. Seasonality was considered with a spline function in the overall analyses (individual months) or with a categorical variable (quarterly periods) when applicable.
Plots were produced using observed, counterfactual, and fitted values. If the counterfactual did not follow the baseline trend, the model was modified (i.e., the number of degrees of freedom for splines was reduced) until the counterfactual was consistent with the baseline trend. COVID-19-by-time interactions were considered if the plotted fitted values in the COVID-19 period did not fit the observed data well (e.g., observed values were below fitted values during the early COVID-19 period but higher during the later COVID-19 period). Significant time interactions were found for some diagnostic tests analyzed but still demonstrated poor fit (i.e., fitted values did not fit observed values well). Therefore, we created multiple COVID-19 dummy variables representing different periods during the pandemic to provide a slope for each period enabling more accurate predictions.
March 2020 (or January to March 2020 when data were analyzed by quarter) was excluded from the analyses because COVID-19 restrictions were implemented incrementally throughout March.12–14
Ratios between counterfactual and fitted estimates and 95% confidence intervals (CIs) derived from contrast statements were calculated. The estimated cumulative difference in the number of tests during the pandemic was calculated and plotted using a forest plot. The 95% CIs for the cumulative difference estimates were calculated with parametric bootstrapping and 1000 replications.
Data analyses were performed in SAS Version 9.4 (SAS Institute Inc., Cary, NC, USA) and R Version 4.1.30.5 (R Foundation for Statistical Computing, Vienna, Austria). The following R packages were used: haven, splines, Hmisc, lattice, MASS, ggplot2, glmmTMB, car, DHARMa, multcomp, lmtest, quantreg, and forestplot.15–25
This study was approved by the University of Manitoba's Health Research Ethics Board (HS23979; H2020:264), Manitoba Health's Provincial Health Research Privacy Committee (2020/2021-16), the Shared Health Approval Committee for Privacy, Impact and Access in Research Committee (RAAC2020:031) and CCMB's Research and Resource Impact Committee (2020-14). Informed consent was not required. This study follows STROBE reporting guidelines for observational studies.
Results
Test Rates by Month
From January 1, 2015 to August 31, 2022, there were 197 483 bilateral mammograms, 41 052 unilateral mammograms, 47 572 breast ultrasounds, 80 498 colposcopies, and 285 379 colonoscopies performed in Manitoba. Figure 1 shows the observed, counterfactual, and fitted rates per 100 000 and 95% CI of the ratio of the fitted to counterfactual rate for each diagnostic test by month from January 1, 2015 to August 31, 2022 (excluding March 2020).

Rate per 100 000 for (A) bilateral mammograms, (B) unilateral mammograms, (C) breast ultrasounds, (D) colposcopies, and (E) colonoscopies by month from January 1, 2015 to August 31, 2022, Manitoba.
Ratios between fitted and counterfactual test rates by month and 95% CI are provided in Supplemental Table S1. In April 2020, there was a 77% decrease in bilateral mammograms (ratio = 0.23, 95% CI [0.20, 0.28]), a 70% decrease in unilateral mammograms (ratio = 0.30, 95% CI [0.23, 0.40]), a 53% decrease in breast ultrasounds (ratio = 0.47, 95% CI [0.41, 0.53]), a 63% decrease in colposcopies (ratio = 0.37, 95% CI [0.31, 0.45]), and a 75% decrease in colonoscopies (ratio = 0.25, 95% CI [0.21, 0.31]). By June 2020, there was no longer a significant difference between the fitted and counterfactual rates for unilateral mammograms and colposcopies. In August 2022, bilateral mammograms were 8% lower (ratio = 0.92, 95% CI [0.84, 1.01]), breast ultrasounds were 12% lower (ratio = 0.88, 95% CI [0.83, 0.93]), and colonoscopies were 9% lower (ratio = 0.91, 95% CI [0.82, 1.00]) than expected.
Test Rates by Month and Age Group
Ratios by age group and 95% CI are provided in Supplemental Table S2 and Supplemental Figure S1. The rate of diagnostic tests decreased for all age groups in April to June 2020. In April to June 2022, bilateral mammograms were 11% lower for the 50 to 74 age group (ratio = 0.89, 95% CI [0.85, 0.94]), unilateral mammograms were 12% lower for the ≥75 age group (ratio = 0.88, 95% CI [0.82, 0.95]), and breast ultrasounds were 12% (ratio = 0.88, 95% CI [0.82, 0.95]), 10% (ratio = 0.90, 95% CI [0.83, 0.98]), and 19% (ratio = 0.91, 95% CI [0.69, 0.95]) lower for the <50, 50 to 74, and ≥75 age groups, respectively. There was no difference between the fitted and counterfactual rates for colposcopy. Colonoscopy rates were significantly lower than the counterfactual for all age groups (11% for the <50 and 50-74 age groups and 8% for the ≥75 age group). Supplemental Table S3 and Figure 2 show colonoscopy ratios by sex. In April 2020, the decrease in the rate of colonoscopy was 64% (ratio = 0.36, 95% CI [0.30, 0.44]) for males and 70% (ratio = 0.30, 95% CI [0.24, 0.36]) for females. As of August 2022, the decrease was 10% (ratio = 0.90, 95% CI [0.84, 0.96]) for males and 12% for females (ratio = 0.88, 95% CI [0.83, 0.94]).

Estimated cumulative difference and percent cumulative difference between the fitted and counterfactual number of bilateral mammograms, unilateral mammograms, breast ultrasounds, colposcopies, and colonoscopies as of August 31, 2022, Manitoba.
Figure 2 shows the estimated cumulative difference and percent cumulative difference by test type between the fitted and counterfactual number of tests.
As of August 31, 2022, there were an estimated 7270 (10.7%) fewer bilateral mammograms, 2722 (14.8%) fewer breast ultrasounds, 836 (3.3%) fewer colposcopies, and 11,600 (13.8%) fewer colonoscopies than expected in the absence of COVID-19. As of June 30, 2022, the percent cumulative deficit was highest for bilateral mammograms in the 50 to 74 age group (14.8% deficit), breast ultrasounds in the 70+ age group (21.5% deficit), and colonoscopies in the 50 to 74 age group (15.4% deficit) (Supplemental Table S4). The colonoscopy percent cumulative deficit was similar for males and females.
Colonoscopy Rates by Month and Referral status
We also examined the rate of colonoscopies for the WRHA by referral status. From January 1, 2018 to December 31, 2022, there were 88 411 colonoscopies; 58 519 were classified as elective, 25 993 were semiurgent, and 3899 were urgent. Figure 3 shows the fitted and counterfactual colonoscopy rates per 100 000 and 95% CI of the ratio of the fitted to counterfactual rate by month and referral status.

Rate per 100 000 for colonoscopies by month for (A) elective, (B) semiurgent, and (C) urgent referrals from January 1, 2018 to December 31, 2022, Winnipeg. *includes Winnipeg and surrounding communities of East St. Paul, West St. Paul, Headingly East, and Headingly West, scheduled and completed colonoscopies.
Ratios between fitted and counterfactual test rates by month and 95% CI are provided in Supplemental Table S5. In April and May 2020, the rate of elective colonoscopies decreased by 76% (ratio = 0.24, 95% CI [0.16, 0.35]). From June 1, 2020 to December 31, 2021, the rate of elective colonoscopies remained 20% (ratio = 0.80, 95% CI [0.67, 0.94]) lower than expected. In April and May 2020, the rate of semiurgent colonoscopies also decreased by 39% (ratio = 0.61, 95% CI [0.50, 0.73]). However, there was no significant decrease from June 30, 2020 to December 31, 2021. There was no decrease in the rate of urgent colonoscopies in April 2020. In May, the rate of urgent colonoscopies doubled (ratio = 2.05, 95% CI [1.5, 2.79]). From June 30, 2020 to December 31, 2021, the rate of urgent colonoscopies ranged from 23% to 29% above expected. By December 2022, cumulatively, there were an estimated 6030 (23.9%) fewer elective colonoscopies, 313 (2.6%) fewer semiurgent colonoscopies, and a surplus of 438 (27.3%) urgent colonoscopies in the WRHA.
Figure 4 shows the observed, counterfactual, and fitted mean number of days from referral date to colonoscopy date by month from January 1, 2015 to October 31, 2021 for elective colonoscopies and December 31, 2022 for semiurgent and urgent colonoscopies (excluding March 2020).

Mean number of days from referral date to colonoscopy date for (A) elective, (B) semiurgent, and (C) urgent referrals from January 1, 2018 to October 31, 2022, Winnipeg. *includes Winnipeg and surrounding communities of East St. Paul, West St. Paul, Headingly East, Headingly West, scheduled and completed colonoscopies.
Ratios between the fitted and counterfactual mean number of days by month and 95% CI are provided in Supplemental Table S6.
Days from Referral to Colonoscopy by Referral Type
Supplemental Table S7 shows the median number of days and the 90th percentile. Individuals who were referred for colonoscopy prior to COVID-19 but had a colonoscopy after the start of COVID-19 and extreme outliers (values above 1.5 × 75th percentile value) were excluded. 26 Elective colonoscopies were analyzed until October 31, 2021 to allow for complete information on time from referral to performance of colonoscopy. As of October 31, 2021, the mean number of days from referral date to colonoscopy date for elective referrals was 261 days compared to 79 days for the counterfactual (the mean number of days expected in the absence of COVID-19 based on the pre-COVID-19 time period) (ratio = 3.32, 95% CI [3.04, 3.62]). As of December 31, 2022, the mean number of days from referral date to colonoscopy date was 52 for semiurgent referrals compared to the counterfactual of 39 days (ratio = 1.53, 95% CI [1.38, 1.67]) and 11 days for urgent referrals (the same as the counterfactual, ratio = 1.00, 95% CI [0.92, 1.09]).
Discussion
The impact of the COVID-19 pandemic on the provision of health care continues to emerge. In Manitoba, the rate of diagnostic tests for breast, colorectal, and cervical cancers decreased significantly at the start of the pandemic. Within a few months, unilateral mammogram and colposcopy rates returned to normal for all age groups. Two and a half years after the initial implementation of changes to the health care system to cope with the pandemic, the rate of bilateral mammograms, breast ultrasounds, and colonoscopies remained lower than expected in Manitoba. To fully recover from the pandemic, the healthcare system may need to implement new strategies to increase capacity above prepandemic levels.
Studies from other jurisdictions also reported large decreases in diagnostic mammograms at the start of the pandemic. Nyante et al. used an ITS analysis to examine the impact of the pandemic on diagnostic mammograms in 7 imaging facilities in the University of North Carolina Health System. 27 They found significantly lower diagnostic mammograms than expected in March and April of 2020. The diagnostic mammogram rate reached expected levels after May 2020, and there was no significant difference between observed and expected diagnostic mammograms by July 2020. Song et al. examined the impact of the pandemic on diagnostic mammograms in the United States using a pre–post study design and data from a private health insurer. 28 They also found a large decrease in diagnostic mammograms at the start of the pandemic which returned to expected levels by July 2020. In Manitoba, the rate of bilateral mammograms remained consistently below the counterfactual for women 50 to 74 years of age resulting in a deficit of 6175 tests as of June 2022. Breast ultrasounds were lower than expected for all age groups. In Winnipeg, breast ultrasounds are primarily provided by one private imaging clinic which, similar to the rest of the healthcare system, is operating with a deficit of healthcare providers. It is possible that individuals who experience longer wait times will have poorer breast cancer outcomes (i.e., tumors that have progressed or metastasized). Because both bilateral mammograms and breast ultrasounds in Manitoba are continuously triaged by risk and urgency, hopefully the risk of poorer outcomes is low. Nevertheless, strategies are needed to address this backlog because long wait times have other important negative consequences for patients such as increased anxiety and eroded trust in the healthcare system. 29
Overall reductions in colonoscopy have also been reported elsewhere. Emara et al. conducted a systematic review of the impact of COVID-19 on gastrointestinal endoscopy that included the United States, Italy, China, and Egypt. 30 They found reductions of 75% to 100% early in the pandemic in all countries. We also found differences in the colonoscopy rate in the city of Winnipeg but this depended on referral status. The rate of urgent referrals did not significantly decrease in April 2020, which is reassuring. Urgent referrals then doubled in May 2020 likely because some individuals who were considered semiurgent in April and May were reclassified in June as urgent. Unfortunately, a large deficit persists for elective colonoscopies in Winnipeg. Elective colonoscopies include screening for individuals who are above average risk for CRC, post-CRC treatment surveillance, and unexplained mild rectal bleeding. The average wait time was under 150 days before the pandemic but reached more than 250 days 18 months after the start of the pandemic. It is possible that longer wait times for a colonoscopy may lead to some individuals being diagnosed with CRC at a later stage.31,32 However, because screening and routine surveillance identifies only approximately 20% of CRCs 33 and the remaining are symptomatic, the risk maybe low for individuals for whom a colonoscopy is elective if appropriate triaging is performed for symptoms and signs such as ongoing rectal bleeding and iron deficiency anemia.
To help manage the colonoscopy backlog, on January 19th, 2022, the Manitoba government started replacing the Hemoccult Sensa with a fecal immunochemical test (FIT) which can also be used instead of an elective colonoscopy in some situations such as the surveillance of low-risk colon polyps (less than 3 tubular adenomas) or a positive family history (single first-degree relative diagnosed with CRC above the age of 60). 34 On April 19th, 2022, the provincial CRC screening program began to distribute FIT to consenting eligible patients on the elective colonoscopy waitlist.35,36 This also includes patients awaiting opportunistic primary colonoscopy screening as well as surveillance of those with lower risk. A similar strategy was implemented in Ontario in June 2020 which recommended that individuals originally scheduled for low-yield colonoscopies (i.e., average-risk screening colonoscopy or surveillance colonoscopy in those with a history of low-risk adenomas) have an FIT instead.37,38 It will take several years before we can evaluate the impact of this strategy on wait times and patient outcomes. Patient and healthcare providers’ uptake of this strategy also needs evaluation. Unfortunately, FIT was not available to those not on the colonoscopy wait list until July 2023, which may have limited the impact of its introduction. Other strategies more recently being pursued include increasing colonoscopy capacity above historical volumes at least for some time (a costly and challenging strategy), and developing an endoscopy wait-list system across the entire province. 39
This study has several strengths and weaknesses. We used population-based, high-quality administrative health data. The ITS analysis had a long preintervention period which permitted the evaluation of outcomes before the start of the COVID-19 pandemic and the inclusion of seasonality and interactions between COVID-19 pandemic onset and time in the analysis. 9 We included data until June or August 2022 which encompasses 6 pandemic waves. We were not able to include breast ultrasounds done at one Winnipeg facility leading to an undercount for this test. However, this undercounting will likely have remained constant over time. Because the analysis that calculated the wait time from referral date to colonoscopy date could only include data to October 2021, we could not measure the early impact of strategies such as FIT to reduce the colonoscopy waitlist. We did not examine the association between COVID-19 and the rate of diagnostic tests by income quintile. This work is important because research has found that people who live in lower-income neighborhoods are less likely to have a mammogram or colonoscopy,39,40 and more likely to experience diagnostic delays following abnormal breast or colorectal cancer screening tests. The pandemic likely worsened this situation. 41 We are currently working on this analysis. Lastly, because the association between COVID-19 and diagnostic tests may differ between jurisdictions, our results must be interpreted within the Manitoba context. Population-based studies should be performed elsewhere that consider pre-COVID-19 trends in cancer diagnostic tests and include sufficient follow-up time.
Conclusions
Healthcare systems had to balance providing care for individuals diagnosed with COVID-19 while caring for others with healthcare needs and keeping patients and healthcare providers safe. In Manitoba, this was associated with an initial decrease in diagnostic mammograms, breast ultrasounds, colposcopies, and colonoscopies. Two and a half years later, the rate of bilateral mammograms, breast ultrasounds, and colonoscopies remained lower than expected. The rate of colposcopies and unilateral mammograms returned to normal. As we move beyond the pandemic, studies are needed to assess the reasons for these deficits in diagnostic tests so that strategies can be implemented to increase uptake.
Supplemental Material
sj-docx-1-tct-10.1177_15330338241263616 - Supplemental material for Examining the Association Between the COVID-19 Pandemic and the Rate of Diagnostic Tests for Breast, Cervical, and Colorectal Cancer in Manitoba, Canada
Supplemental material, sj-docx-1-tct-10.1177_15330338241263616 for Examining the Association Between the COVID-19 Pandemic and the Rate of Diagnostic Tests for Breast, Cervical, and Colorectal Cancer in Manitoba, Canada by Kathleen M. Decker, Grace Musto, Oliver Bucher, Piotr Czaykowski, Pamela Hebbard, Julian O. Kim, Harminder Singh, Maclean Thiessen, Allison Feely, Katie Galloway and Pascal Lambert in Technology in Cancer Research & Treatment
Footnotes
Abbreviations
Acknowledgments
We gratefully thank Kelly Brown and Gary Annable for study coordination. We also thank Dr. Dana Moffatt, Shared Health Co-Director of Endoscopy and Carrie Loewen, Manager of Endoscopy Services for the Winnipeg Regional Health Authority for reviewing this manuscript and Kym Morris for providing Winnipeg Regional Health Authority Central endoscopy data.
Author Contribution Statement
Conceptualization: Decker, Lambert, and Bucher; data curation: Lambert and Musto; formal analysis: Decker, Musto, Lambert, Feely, Galloway, and Bucher; funding acquisition: Decker, Lambert, Bucher, Hebbard, Kim, Czaykowski, Singh, and Thiessen; methodology: Decker, Lambert, Musto, Bucher, Feely, and Galloway; project administration: Decker; supervision: Decker; writing—original draft: Decker, Lambert, and Musto; writing—review and editing: all authors. All authors have read and agreed to the published version of the manuscript.
Data Availability Statement
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethics
This study was approved by the University of Manitoba's Health Research Ethics Board (HS23979; H2020:264), Manitoba Health's Provincial Health Research Privacy Committee (2020/2021-16), and CCMB's Research and Resource Impact Committee (2020-14). Informed consent was not required. This study follows STROBE reporting guidelines for observational studies. Because data were deidentified, informed consent was not required.
Funding
This work was supported by a research grant from Research Manitoba and the CancerCare Manitoba Foundation (2020 to 2021, Grant No. 4459) and the Canadian Institutes of Health Research (2022-2024, Grant No. 179890).
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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