LBW indicates low birth weight; SIDS, sudden infant death syndrome.
eTable 1. ICD-10 Codes for Specific Causes of Death
eTable 2. Average Annual Percent Changes in mortality rates for the U.S., Canada and England/Wales, 1999-2015
eTable 3. Average annual percent change for all-cause mortality by age and race/ethnicity in the U.S.
eTable 4. Absolute Change in All-Cause Mortality between 1999-2002 & 2012-2015
eTable 5. Absolute Change for Leading Causes of Infant Mortality between 1999-2002 & 2012-2015
eTable 6. Absolute Change for Specific Causes of Unintentional Injury Mortality in Infants between 1999-2002 and 2012-2015
eTable 7. Absolute Change for Leading Causes of Youth Mortality between 1999-2002 & 2012-2015
eTable 8. Absolute Change for Specific Causes of Unintentional Injury Deaths in 20-24-year-olds between 1999-2002 and 2012-2015
eTable 9. Absolute Change for Means of Suicide between 1999-2002 and 2012-2015
eFigure 1. Non-Leading Causes of Death for White, Black and Latino Infants
eFigure 2. Absolute rate change between 1999-2002 and 2012-2015 for leading causes of death for White, Black and Latino A) 1-9-year-olds and B) 10-14-year-olds, and C)15-19-year-olds. All rates are expressed per 100,000
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Khan SQ, Berrington de Gonzalez A, Best AF, et al. Infant and Youth Mortality Trends by Race/Ethnicity and Cause of Death in the United States. JAMA Pediatr. 2018;172(12):e183317. doi:10.1001/jamapediatrics.2018.3317
How have infant and youth mortality trends changed in the United States between 1999 to 2015 by age, race/ethnicity, and cause of death?
All-cause mortality rates decreased in most age and racial/ethnic groups, and declines occurred for major causes of death including sudden infant death syndrome in infants and homicide and unintentional injury deaths in youth. In contrast, mortality rates from suffocation and strangulation in bed in infants and suicide and drug poisonings in youth increased over time.
Resources should be allocated toward the prevention of suicide and drug poisoning in youth, and safe sleep techniques should be reinforced for infants.
The United States has higher infant and youth mortality rates than other high-income countries, with striking disparities by racial/ethnic group. Understanding changing trends by age and race/ethnicity for leading causes of death is imperative for focused intervention.
To estimate trends in US infant and youth mortality rates from 1999 to 2015 by age group and race/ethnicity, identify leading causes of death, and compare mortality rates with Canada and England/Wales.
Design, Setting, and Participants
This descriptive study analyzed death certificate data from the US National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. The study took place from January 1, 1999, to December 31, 2015, and analyses started in September 2017.
Main Outcomes and Measures
Average annual percent changes in mortality rates from 1999 to 2015 and absolute rate change between 1999 to 2002 and 2012 to 2015 for each age group, race/ethnicity, and cause of death.
Among individuals from birth to age 24 years, 1 169 537 deaths occurred in the United States, 80 540 in Canada, and 121 183 in England/Wales from 1999 to 2015. In the United States, 64% of deaths occurred in male individuals and 52.6% occurred in white individuals (25.1% deaths occurred in black individuals and 17.9% in Latino individuals). All-cause mortality declined for all age groups (infants younger than 1 year [38.5% of deaths], children aged 1-9 years [10.6%], early adolescents aged 10-14 years [5%], late adolescents aged 15-19 years [17.7%], and young adults aged 20-24 years [28.1%]) in the United States, Canada, and England/Wales from 1999 to 2015. However, rates were highest in the United States. Within the United States, annual declines in all-cause mortality rates occurred among all age groups of black, Latino, and white individuals, except for white individuals aged 20 to 24 years, whose rates remained stable. Mortality rates declined across most major causes of death from 1999 to 2002 and 2012 to 2015, with notable declines observed for sudden infant death syndrome, unintentional injury death, and homicides. Among infants, unintentional suffocation and strangulation in bed increased (difference between 2012-2015 and 1999-2002 range, 6.11-29.03 per 100 000). Further, suicide rates among Latino and white individuals aged 10 to 24 years (range, 0.21-2.63 per 100 000) and black individuals aged 10 to 19 years (range, 0.10-0.45 per 100 000) increased, as did unintentional injury deaths in white young adults (0.79 per 100 000). The rise in unintentional injury deaths is attributed to increases in drug poisonings and was also observed in black and Latino young adults.
Conclusions and Relevance
Mortality rates in the United States have generally declined for infants and youths from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury death, and homicides. However, US mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among US adolescents and young adults.
Since the 1960s, infant (younger than 1 year) and youth (age 1 to 24 years) mortality rates have declined worldwide.1,2 In the early 20th century, childhood deaths accounted for one-third of all deaths in the United States compared with less than 2% in 2015.3,4 Infant and youth mortality rates in the United States are notably higher than other high-income countries, despite having the highest health expenditures per capita in the world.2,5-7 There are also pronounced racial/ethnic disparities within the United States.8,9 In 2015, black infants were 2.3-times more likely to die than white infants.3,10 Similarly, mortality rates among black adolescents and young adults were 50% higher than rates for their white counterparts, primarily owing to higher rates of homicide.3 Recently, mortality rates due to drug poisonings and suicides have increased among adolescents and young adults in the United States,11,12 although it is unclear whether rates have increased equally across races/ethnicities and how these increases have influenced overall trends in mortality rates.
Detailed understanding of mortality trends in infants and youth are essential to understand where progress has been made and to target future public health efforts. Previous studies that have focused on mortality trends among US youth have not comprehensively examined differences by race/ethnicity, age group, and cause of death.13,14 The current study provides a detailed characterization of trends in infant and youth mortality between 1999 to 2015 by age group and race/ethnicity, identifies leading causes of death contributing to these trends, and compares mortality rates with Canada and England/Wales.2,15 Understanding changing trends in infant and youth mortality will provide insight regarding which causes of death and demographic groups should be priorities for interventions.
Institutional review board approval and patient consent were not needed because publicly available data were used. Mortality and population data from the United States were obtained from death certificates from the US National Center for Health Statistics, Centers for Disease Control and Prevention, and the US Census Bureau, respectively. Mortality and population data from Canada and England/Wales were obtained from Statistics Canada and the UK Office for National Statistics, respectively.16,17 Canada and England/Wales were selected owing to basic similarities with the United States, including advanced economies, modern health care systems, and primarily white populations that are progressively becoming more diverse via immigration. Causes of death were coded with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, and categorized with Surveillance, Epidemiology, and End Results death recode variables for individuals aged 1 to 24 years and with the US National Center for Health Statistics 130 Selected Causes of Infant Death. Surveillance, Epidemiology, and End Results recodes individual International Statistical Classification of Diseases and Related Health Problems codes into groups for consistent analysis over time (https://seer.cancer.gov/codrecode/index.html). Race/ethnicity of each decedent was also ascertained from death certificates and classified as Asian and Pacific Islander (API), American Indian/Alaskan Native (AI/AN), non-Hispanic black or African American (black), Hispanic or Latino (Latino), and non-Hispanic white (white). Analyses for AI/AN were restricted to counties in Contract Health Services Delivery Areas to increase the sensitivity of AI/AN classification on death certificates.18
All-cause mortality rates were estimated by age group (<1, 1-4, 5-9, 10-14, 15-19, and 20-24 years) for the United States, Canada, and England/Wales from 1999 to 2015. Mortality rates for each age group in the United States were further stratified by race/ethnicity. Individuals aged 1 to 4 years and 5 to 9 years had similar leading causes of death and trends and were therefore collapsed for the US analyses to increase sample size and age-standardized in 5-year age groups to the 2000 US population.
We used the Joinpoint Regression Program (version 4.5.0., SEER*Stat) to estimate the average annual percent changes (AAPCs) in all-cause and cause-specific mortality rates from 1999 to 2015. Average annual percent changes were estimated by age group in the United States, Canada, and England/Wales and by race/ethnicity and cause of death in the United States.
To identify specific causes of death driving changes in age-specific mortality rates, we estimated the absolute difference in all-cause and cause-specific mortality rates between 1999 to 2002 and 2012 to 2015 for the 5 leading causes of death by age and race/ethnicity for black, Latino, and white individuals. Individuals in the API and AI/AN groups were excluded from cause-specific analyses owing to sparsity of data. We further stratified causes of death observed to be increasing into more specific subgroups (eTable 1 in Supplement 1).
For total mortality and causes of death in which mortality rates increased over time, excess deaths were estimated by subtracting the observed number of deaths from the number of deaths expected if rates remained constant. The expected number of deaths were calculated by applying 1999 to 2002 age-specific mortality rates to the 2015 population. This approach conservatively estimates the number of excess deaths, as ideally rates would decline, not remain stable, over time.
In the United States, Canada, and England/Wales, mortality rates decreased in all age groups from 1999 to 2015 (AAPCs, −0.82% per year to −4.01% per year; all P < .05) (Figure 1). However, the United States had higher mortality rates compared with Canada and England/Wales for all age groups across the time period. Differences between mortality rates in the United States and Canada narrowed over time for all age groups except individuals aged 5 to 9 years and 20 to 24 years, for whom rates diverged (Figure 1). In contrast, differences between mortality rates in the United States and England/Wales widened for all age groups over time owing to rates declining more rapidly in England/Wales than the United States. For example, mortality rates among young adults in England/Wales declined by 3.69% per year (95% CI, −4.2 to −3.2) but only by 0.82% per year (95% CI, −1.3 to −0.3) in the United States (eTable 2 in Supplement 1). The greatest disparity observed was in 2015 for individuals aged 20 to 24 years, where the mortality rate was 2.5-times higher in the United States than in England/Wales (89.5 vs 35.5 per 100 000) (Figure 1).
In the United States, black infants had the highest all-cause mortality rate (1128/100 000) compared with all other races/ethnicities (AI/AN, 968/100 000; white, 498/100 000; Latino, 466/100 000; API, 390/100 000) (Figure 2). In all other age groups, AI/ANs had the highest mortality rates, and APIs had the lowest. Of note, only APIs had mortality rates that were lower than Canada and comparable with England/Wales in 2015 (Figure 1 and Figure 2). Mortality rates in all other US races/ethnicities were notably higher (eTable 3 in Supplement 1).
From 1999 to 2015, API, black, and Latino individuals had significant annual declines in all-cause mortality rates in every age group (AAPCs, −1.84% per year to −3.81% per year; all P < .05) (eTable 3 in Supplement 1). In contrast, all-cause mortality rates among AI/ANs were stable across all age groups, except individuals aged 15 to 19 years, in which significant annual declines occurred (AAPC, −1.93%; 95% CI, −2.9 to −1.0). Among white individuals, there were significant annual declines for all age groups (AAPCs, −1.21% per year to −2.84% per year; all P < .05) except individuals aged 20 to 24 years, whose rates remained stable. Absolute declines in all-cause mortality among all races/ethnicities resulted in an estimated 12 000 fewer deaths in infants and youth in 2015, compared with what was expected based on the rates from 1999 to 2002 (eTable 4 in Supplement 1).
Figure 3 and eTables 4 and 5 in Supplement 1 show the absolute changes in mortality rates for black, Latino, and white infants between 1999 to 2002 and 2012 to 2015 for the 5 leading causes of death. Absolute mortality rates declined among black (−318.70/100 000), Latino (−92.28/100 000), and white (−83.75/100 000) infants, largely driven by declines in sudden infant death syndrome (SIDS) (range, −49.94 to −13.10 per 100 000) and congenital malformations (range, −25.31 to −19.73 per 100 000) among all 3 races/ethnicities, and short gestation/low birth weight among black individuals (−58.25/100 000). Black, Latino, and white infants also had notable declines in nonleading causes of death (eFigure 1 in Supplement 1). In contrast, there were increases in unintentional injury deaths among black (18.3/100 000) and white (7.60/100 000) infants and in deaths due to maternal complications of pregnancy among Latino infants (8.99/100 000) (Figure 3A).
We investigated specific causes of death driving the increase in unintentional injury deaths among infants. Mortality rates due to unintentional transport injuries decreased for all races/ethnicities between 1999 to 2002 and 2012 to 2015 (black, −3.30/100 000; Latino, −3.04/100 000; white, −1.68/100 000) (Figure 4A and eTable 6 in Supplement 1). However, mortality rates due to unintentional suffocation and strangulation in bed increased in all races/ethnicities (black, 29.03/100 000; Latino, 6.11/100 000; white, 11.63/100 000), resulting in approximately 560 additional deaths in 2015 compared with what was expected based on rates from 1999 to 2002.
For children, mortality rates decreased in all races/ethnicities for all leading causes of death between 1999 to 2002 and 2012 to 2015 (eFigure 2A and eTables 4 and 7 in Supplement 1). The largest absolute decline was for unintentional injury deaths (−4.66 to −2.61 per 100 000). Declines were also observed for congenital malformations, heart disease, homicide, and malignancies.
All-cause mortality rates declined between 1999 to 2002 and 2012 to 2015 among individuals aged 10 to 14 years for all races/ethnicities largely due to declines in unintentional injury death rates (black, −4.30/100 000; Latino, −2.59/100 000; white, −3.92/100 000) (eFigure 2B and eTables 4 and 7 in Supplement 1). Mortality due to chronic lower respiratory disease, congenital malformations, heart disease, homicide, and malignancies also declined. However, suicide mortality rates increased slightly in all 3 groups (black, 0.45/100 000; Latino, 0.21/100 000; white, 0.80/100 000).
Declines between 1999 to 2002 and 2012 to 2015 in all-cause mortality rates occurred among black, Latino, and white individuals aged 15 to 19 years, largely driven by declines in unintentional injury mortality (range, −16.8 to −9.1 per 100 000) in all races/ethnicities and homicide mortality rates (range, −7.5 to −5.1 per 100 000) for black and Latino individuals (eFigure 2B and eTables 4 and 7 in Supplement 1). Declines were also observed in heart disease and malignancy mortality rates. As with early adolescents, suicide mortality rates increased slightly among late adolescents (black, 0.10/100 000; Latinos, 0.39/100 000; white, 1.86/100 000).
While all-cause mortality rates declined substantially among black and Latino young adults between 1999 to 2002 and 2012 to 2015 (range: −33.17 to −16.62 per 100 000), rates among white young adults increased slightly (0.21/100 000) (Figure 3B and eTable 4 in Supplement 1). Declines among black and Latino individuals were largely due to decreases in unintentional injury death and homicide rates. Heart disease and malignancy mortality rates decreased across races/ethnicities. Whereas suicide rates among black young adults decreased (−0.36/100 000), rates among white (2.63/100 000) and Latino (2.18/100 000) individuals increased. Unintentional injury death rates also increased among white individuals (0.79/100 000).
Among the major causes of unintentional injury deaths in young adults, deaths due to motor vehicle, other transport, and other nontransport injuries decreased notably across all races/ethnicities, resulting in net decreases in unintentional injury mortality rates in black and Latino individuals (Figure 4B and eTable 8 in Supplement 1) between 1999 to 2002 and 2012 to 2015. However, deaths due to unintentional drug poisonings increased in white (11.70/100 000), black (1.76/100 000), and Latino (3.18/100 000) young adults, resulting in an overall increase in these death rates for white individuals. Rising rates of deaths due to unintentional drug poisonings resulted in an estimated 2100 additional deaths in 2015 over what would have been expected had rates remained stable.
We examined changes in the causes of suicide between 1999 to 2002 and 2012 to 2015 among individuals aged 15 to 19 years and 20 to 24 years (Figure 5 and eTable 9 in Supplement 1). Suicide rates by firearms increased slightly in white individuals aged 15 to 24 years (range, 0.14-0.51 per 100 000) but decreased for black and Latino individuals aged 15 to 24 years. Suicide rates from hanging (range, 1.00-1.95 per 100 000) and drug poisoning (range, 0.06-0.27 per 100 000) increased in all 3 races/ethnicities, with the greatest increases in intentional drug poisoning observed in black and Latino young adults. Rising suicide rates resulted in approximately 1400 additional deaths in 2015 compared with what would have been expected if rates remained stable.
From 1999 to 2015, there were substantial declines in all-cause and cause-specific mortality rates in US infants and youth in most age and racial/ethnic groups. By 2015, the United States surpassed Healthy People 2020 goals for a 10% reduction in infant and youth mortality in almost all age groups. Declines are largely attributed to reductions in SIDS and congenital malformations in infants and homicide and unintentional injuries in youth, resulting in approximately 12 000 total averted deaths in 2015, compared with what would have been expected if mortality rates remained stable. Unfortunately, mortality rates remain substantially higher than those in Canada and England/Wales and racial disparities are pronounced. Further, increasing mortality rates were observed for unintentional suffocation and strangulation in bed among infants, and suicide and drug poisonings in adolescents and young adults, resulting in approximately 4000 additional deaths in 2015.
Previous studies observed higher youth mortality rates in Canada and England/Wales than other high-income countries.15 Although mortality rates in US children have improved markedly, they remain even higher and are improving more slowly than in Canada and England/Wales. Further, long-standing racial/ethnic disparities in the United States persist.8,9,19,20 Black individuals had the largest absolute declines in mortality rates in each age group examined; however, in 2015, mortality rates were still higher among black than white individuals across age groups, even among young adults where no improvements were observed among white individuals. These disparities are a result of long-standing social and economic inequality, which influences access of care, quality of care, and attitudes of patients and clinicians.21 The highest mortality rates were consistently observed among AI/ANs, except among infants. Previous studies have attributed elevated mortality rates in AI/ANs to unintentional injury, alcohol and substance use, homicide, and suicide.22-24 Additionally, AI/AN communities often have high levels of poverty, unemployment, and limited access to quality education and health care.22,25-27
The United States ranks among the lowest of all high-income countries for infant health.2,6,28 The preterm birth rate in the United States is particularly high, and prematurity is a major cause of infant mortality.29,30 The high infant mortality rate in the United States reflects poor maternal health, high adolescent birth rates, and limited access to prenatal care for the socially disadvantaged.31,32 The largest absolute disparities internationally and within the United States were observed for infant mortality. Although the infant mortality rate declined by 20% from 1999 to 2015 (7.36 to 5.90 per 1000), achieving the Healthy People 2020 goal of less than 6 deaths per 1000 infants, 2015 infant mortality rates remained exceptionally high and far from this goal for black individuals (11/1000) and AI/ANs (9.7/1000). There have been substantial declines in low-birth-weight deaths among black infants and congenital malformation and SIDS deaths among all infants, which have been attributed to the 1994 Back-to-Sleep campaign recommending babies lay supine when sleeping.33 Interestingly, our study, as well as others, identified an increase in unintentional suffocation and strangulation in bed in infants across all 3 race/ethnicites.34 This increase may be driven by reclassification of SIDS-related deaths due to improvements in death scene investigation protocol allowing for more accurate cause of death coding.33,35-38 The number of infant deaths from SIDS remains high, and safe sleep techniques should be reinforced for all infants. We also note that deaths rates due to maternal complications of pregnancy in Latino infants have increased, which warrants further investigation.
Mortality rates among children of all 3 races/ethnicities declined, with the largest declines observed for unintentional injury deaths, attributed to fewer motor vehicle injuries and drownings in previous studies.39,40 Reductions in mortality due to congenital malformations, heart disease, homicide, and cancer also contributed to overall declines.
Among adolescents and young adults in the United States, reductions in unintentional injury and homicide mortality rates contributed substantially to the overall decline in all-cause mortality rates. However, youth mortality rates are higher in the United States than other high-income countries primarily due to higher rates of injury-related deaths, including motor vehicle–related and firearm-related deaths,2,41 which have been increasing in adolescents since 2013.42 Between 2001 and 2012, the firearm-homicide rate among individuals aged 15 to 29 years was 82-times higher in the United States than 19 other high-income countries and increased by about 25% between 2012 to 2014.2,42 Within the United States, black teenagers have even higher homicide and firearm mortality rates than their white and Latino counterparts.8,43-45
Of concern, we found a rise in suicide rates among adolescents and young adults across all races/ethnicities, resulting in more than 1700 additional deaths in 2015 compared with what was expected based on rates from 1999 to 2002. Suicides in adolescents have been observed to be increasing since 2007.42 These data do not include nonfatal suicide attempts, which increased almost 19% annually between 2001 to 2015 in individuals aged 10 to 24 years.46 The firearm-suicide rate in the United States is 8-times higher than other high-income countries.41,47 Although previous work has reported decreasing trends in youth suicide by firearms, we have shown that rates actually increased among white youth.48-52 Consistent with prior studies, we found that suicide by hanging and drug poisoning increased in all 3 races/ethnicities and age groups.49,50,52 The American Academy of Pediatrics published guidelines to assist physicians with identifying and treating depression in youth.53,54 Our data show the importance of these recommendations.
The US opioid epidemic is responsible for reducing life expectancy and increasing premature mortality in white adults.55 Increases in drug-related deaths have been observed in adults across all races/ethnicites.56 In 2010, the Centers for Disease Control and Prevention reported that for each prescription-related opioid death in the United States, there were 108 individuals who abused or were dependent on opioids and 733 nonmedical users of opioids.57,58 Hospitalizations due to nonfatal drug poisonings increased by 65% between 1999 to 2006.59 In 2014, approximately 53 000 hospitalizations and 92 000 emergency department visits occurred for unintentional, opioid-related poisonings alone.60 Young adults had the highest rate of emergency department visits for prescription opioid poisoning.57,61 We found increases in drug poisoning death rates among black, Latino, and white individuals aged 20 to 24 years. Rising rates of drug poisoning deaths resulted in approximately 2100 unintentional deaths in 2015.
The main strength of our study is the comprehensive analysis of infant and youth mortality rates by age, race/ethnicity, and cause of death using data from all deaths in the United States from 1999 to 2015 and comparison with 2 other high-income countries. Limitations include misclassification of the intent of drug poisoning deaths (eg, suicide, unintentional, undetermined intent)62 due to associated stigma, which may underestimate the cause-specific mortality rates and racial/ethnic misclassification on death ceritificates.63 In our data, 5% of all drug poisonings in individuals aged 10 to 24 years had an undetermined intent. To increase the sensitivity of AI/AN ascertainment, we only used counties with health service delivery contracts.18 Further, racial misclassification may have improved over time, which may have led to an underestimation of mortality declines in some groups. Finally, the expected number of deaths were calculated by applying age-specific mortality rates from 1999 to 2002 to the 2015 population; this approach conservatively estimates the number of excess deaths, as ideally rates of all causes of death would decline and not remain stable over the assessed time period.
Despite spending the highest percentage of gross domestic product on health care globally,7 the United States ranks poorly in infant and youth mortality rates. Substantial progress has been made, with reductions in almost all leading causes of death, including unintentional injury, homicide, and malignancies. By 2015, the United States reduced mortality rates below Healthy People 2020 goals in every age group except for young adults. However, striking racial disparities still exist, with black individuals and AI/ANs still far from reaching target goals in certain age groups, with particularly large disparities observed for infant mortality. Furthermore, improvements in mortality rates among young white adults in the United States have stagnated owing to increases in unintentional drug poisonings and suicide. Suicide and drug poisoning rates have also risen for black and Latino youth, highlighting the urgent need for policies and interventions that aim to prevent these deaths.
Corresponding Author: Meredith S. Shiels, PhD, MHS, National Institutes of Health, National Cancer Institute, 9609 Medical Center Dr, Room 6E-218 MSC 9767, Bethesda, MD 20892 (firstname.lastname@example.org).
Accepted for Publication: August 6, 2018.
Published Online: October 1, 2018. doi:10.1001/jamapediatrics.2018.3317
Author Contributions: Ms Khan 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.
Concept and design: Khan, Freedman, Shiels.
Acquisition, analysis, or interpretation of data: Khan, Berrington de Gonzalez, Best, Chen, Haozous, Rodriquez, Spillane, Thomas, Withrow, Freedman, Shiels.
Drafting of the manuscript: Khan, Haozous, Rodriquez, Shiels.
Critical revision of the manuscript for important intellectual content: Khan, Berrington de Gonzalez, Best, Chen, Haozous, Rodriquez, Spillane, Thomas, Withrow, Freedman, Shiels.
Statistical analysis: Khan, Berrington de Gonzalez, Spillane, Shiels.
Obtained funding: Khan, Shiels.
Administrative, technical, or material support: Haozous, Rodriquez, Thomas, Freedman.
Supervision: Berrington de Gonzalez, Shiels.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by the National Institute of HealthIntramural Research Program of the National Cancer Institute and the National Heart, Lung, and Blood Institute as well as the Doris Duke Charitable Foundation (grant 2014194).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, or review; and decision to submit the manuscript for publication. However, the funder did have final approval of the manuscript.
Data Sharing Statement: See Supplement 2.
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