BACKGROUND:Causes of childhood cancer remain poorly understood. Using data from the case-control studies of the Childhood Cancer and Leukemia International Consortium (CLIC), we explored how maternal education as a key socioeconomic status (SES) indicator, varies across studies/countries and contributes to understanding of potential environmental and lifestyle risk factors. METHODS:Control group data from cancer-free children matched by diagnosis date of cases from 16 studies were included, using both interview-based and health registry sources. Maternal education, the primary SES measure used in previous analyses with pooled CLIC data, was categorized as low, medium, or high according to the International Standard Classification of Education. Multinomial logistic regression assessed associations between maternal education and perinatal/lifestyle factors, calculating crude and adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for high vs. low education. RESULTS:Maternal education levels varied across studies and over time, with the highest proportions of highly educated mothers in the U.S. and lowest in Costa Rica, Italy, and Egypt. Higher maternal education was generally positively associated with higher birthweight, breastfeeding, daycare attendance, and maternal prenatal alcohol consumption. Higher maternal education was generally inversely associated with lower birthweight, younger maternal age, paternal occupational pesticide exposure, maternal prenatal smoking, and having more siblings. The direction of associations for older maternal age and for caesarean delivery differed substantially across regions. Exclusion of mothers < 21 years at birth of the index child had little effect on the results. CONCLUSION:This multi-country analysis supports the use of maternal education for adjustment as a proxy for SES, showing largely consistent associations with various behaviors and exposures. While the direction of associations was generally consistent, the strengths varied sometimes considerably by geographical region. These findings support the inclusion of maternal education as a covariate in analyses of childhood cancer risk when pooling CLIC studies.

Childhood cancers are rare, but incidence has risen modestly in countries with robust registration, partly reflecting improved diagnosis. In high-income countries, cancer is the leading cause of disease-related death in children. Marked inequities in incidence, survival, and research capacity underscore the need for large-scale collaboration to identify environmental, genetic, and contextual determinants of risk. The Childhood Cancer and Leukemia International Consortium (CLIC) was established in 2007 to study the etiology of childhood leukemia and later expanded in 2019 to include other childhood cancers, principally solid tumors. CLIC pools harmonized, individual-level data from case-control and cohort studies, obtained through interviews, record linkage (insurance claims, registries), or geographic information systems, and integrates germline genomic data where available. Membership has grown from 13 studies in 9 countries to 57 studies in 21 countries; recruitment spans the early 1960s to the present and encompasses approximately 150,000 cases across all tumor types and 300,000 controls with clinical, demographic, and exposure data, centralized via harmonized data dictionaries at the Data Coordination Center, established in 2014 at the International Agency for Research on Cancer, and supported by a secure analysis platform. Pooled analyses across diverse populations have implicated parental age, prenatal vitamin or folic acid use, mode of delivery, fetal growth, selected congenital anomalies, occupational or household exposures (e.g., pesticides), paternal smoking, and markers of early-life immune modulation (e.g., breastfeeding, daycare attendance) in leukemia risk, informing carcinogen evaluation and prevention. The integration of genetic ancestry and germline susceptibility data is clarifying ancestry-related differences in leukemia biology and outcomes, while confirming risk loci with population-specific effects. CLIC is now adding polygenic risk scores and exposomic data to refine etiologic subtyping and identify modifiable pathways, while broadening representation from underserved regions through partnership-building and capacity-strengthening.

BACKGROUND:Maternal prenatal infections may affect fetal development, increasing the immunological vulnerability of offspring to childhood leukaemia (CL). The role of maternal infections in CL is unclear and might vary by subtype (lymphoblastic, ALL; myeloid, AML) or other characteristics. Understanding this potentially modifiable risk factor could inform prevention strategies. METHODS:Seventeen hospital- and population-based case-control studies of children born in 1972-2019 within the Childhood Cancer and Leukemia International Consortium with self-questionnaires or health-registry data on maternal infection were included (13 638 cases; 26 870 controls). Meta-analyses assessed CL and maternal infection (overall, viral, bacterial, respiratory, influenza/cold, urinary, genital) stratified by subtype, infection timing, race and ethnicity, and diagnosis age. RESULTS:The adjusted meta-analysis odds ratio (OR) for any maternal prenatal infection was 1.13 [95% confidence interval (CI) 0.91-1.40], with similar estimates for ALL and AML. Infection-specific estimates varied. ORs for first-trimester infections were highest for CL and ALL, but not AML, although all CIs contained one. We found modest risk differences between White and Hispanic/Latino children, most notably for CL diagnosed at <2 years (White children: OR 1.25, 95% CI 1.02-1.53; Hispanic/Latino children: OR 0.79, 95% CI 0.34-1.81, subgroup difference P = .05), with similar differences for viral and respiratory/influenza/cold infections. CONCLUSION:Although findings only modestly support an association between maternal prenatal infections and CL, some infections might increase the risk more markedly in young White children compared with Hispanic/Latino children. Risk patterns across race and ethnicity, type, and timing of maternal prenatal infection merit further investigation, as do studies with documented exposure information.

11138 Background: Children with cancer may require substantial healthcare resources during treatment, including inpatient care. Hospital utilization patterns at the population level, and factors associated with higher utilization, are not well-described. Methods: We conducted a retrospective cohort analysis of Washington State (WA) cancer registry data (1992-2013) linked to state birth (1974-2013), death (1992-2013), and hospital discharge (1992-2013) records to identify all WA children diagnosed with cancer <20 years. We examined hospitalization frequency and total inpatient bed days in the year after cancer diagnosis. To evaluate factors associated with outcomes of interest, we constructed multivariable negative binomial regression models of children with ≥1 inpatient admission, calculating incidence rate ratios (IRR). Covariates included rural residence (binary; census tract rural-urban commuting area codes), high neighborhood deprivation (binary; state-normative census block group Area Deprivation Index [ADI]), sex, race/ethnicity, diagnosis age, birth year, and cancer type (per International Classification of Childhood Cancer). Due to differences in utilization by cancer type, we also examined children in subanalyses with acute lymphoblastic leukemia (ALL), lymphomas, and solid (including central nervous system [CNS]) tumors. Results: 2,231 children (mean diagnosis age 7.2 years; 68% diagnosed since 2000) had 12,833 inpatient encounters. In the year after diagnosis, children had a median of 4 (IQR 2-8) hospitalizations/year at-risk, and 21 (IQR 8-54) inpatient days (median length of stay 4 days [IQR 2-6]). In multivariable analysis, high ADI (IRR 1.11, 95% CI 1.01-1.21), but not rural residence (IRR 0.95, 95% CI 0.85-1.05), was associated with greater hospitalization frequency. Female sex was associated with lower frequency (IRR 0.94, 95% CI 0.88-1.00). In analysis of total inpatient days, high ADI (IRR 1.15, 95% CI 1.02-1.29) and Hispanic ethnicity (IRR 1.31, 95% CI 1.13-1.51) were independently associated with greater inpatient days. In subanalysis of patients with ALL (N=497), associations between inpatient days and ADI (IRR 1.18, 95% CI 0.99-1.40) and Hispanic ethnicity (IRR 1.01, 0.84-1.23) were no longer significant. For lymphoma (N=259), associations were similar but also no longer significant (ADI IRR 1.14, 95% CI 0.78-1.71; Hispanic IRR 1.26, 95% CI 0.79-2.10). Among patients with solid/CNS tumors (N=1,151), associations with Hispanic ethnicity remained significant (IRR 1.46, 95% CI 1.19-1.80), but not ADI (IRR 1.11, 95% CI 0.95-1.30). Conclusions: Children with cancer spend considerable time inpatient during the year after diagnosis. Disparities in hospital utilization mirror some known disparities in childhood cancer survival. Initiatives to alleviate systemic disadvantages may reduce inpatient utilization for some groups.

PURPOSE Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer. METHODS We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators. RESULTS On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9). CONCLUSION Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Journal Article Accepted manuscript In Memoriam: Janet R. Daling, 1934-2022 Get access Christopher I Li, Christopher I Li Epidemiology Program, Fred Hutchinson Cancer Research Center Correspondence Address: Christopher I. Li, Fred Hutchinson Cancer Center, 1100 Fairview Avenue N, Seattle, WA 98109. Email: cili@fredhutch.org Search for other works by this author on: Oxford Academic PubMed Google Scholar Noel S Weiss, Noel S Weiss Department of Epidemiology, University of Washington, Seattle Search for other works by this author on: Oxford Academic PubMed Google Scholar Margaret M Madeleine, Margaret M Madeleine Epidemiology Program, Fred Hutchinson Cancer Research Center Search for other works by this author on: Oxford Academic PubMed Google Scholar Beth A Mueller, Beth A Mueller Epidemiology Program, Fred Hutchinson Cancer Research Center Search for other works by this author on: Oxford Academic PubMed Google Scholar Kathleen E Malone Kathleen E Malone Epidemiology Program, Fred Hutchinson Cancer Research Center Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, kwad066, https://doi.org/10.1093/aje/kwad066 Published: 28 March 2023 Article history Received: 10 March 2023 Published: 28 March 2023

Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence. We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95 Breastfeeding was reported by 64.8

OBJECTIVE:To compare obstetric/birth outcomes and rehospitalization among women with and without rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and their infants. METHODS:This population-based retrospective cohort study identified women with RA (n = 1,223) and SLE (n = 1,354) and unexposed women with singleton births 1987-2014 in Washington State in linked vital hospital discharge records. Outcomes, including cause-specific hospitalizations <2 years postpartum, were compared by estimating adjusted relative risks (RRs) and cause-specific rehospitalization hazard ratios (HRs) with 95% confidence intervals (95% CIs). RESULTS:We observed increased risks of several adverse outcomes; RRs were often greatest for SLE. Women with RA/SLE more often required rehospitalization, most notably at <6 months postpartum (RA: 4% versus 2%; RR 2.22 [95% CI 1.62-3.04]; SLE: 6% versus 2%; RR 2.78 [95% CI 2.15-3.59]). Maternal postpartum rehospitalization was greatest for musculoskeletal conditions (RA: HR 19.1 [95% CI 13.6-26.8]; SLE: HR 29.8 [95% CI 22.1-40.1]). Infants of women with SLE more often had malformations (9% versus 6%; RR 1.46 [95% CI 1.21-1.75]), and increased mortality at <2 years (RR 2.11 [95% CI 1.21-3.67]). Infants of women with SLE also experienced more frequent rehospitalizations in their first year of life. CONCLUSION:Women with RA or SLE and their infants experienced adverse outcomes, particularly infants of women with SLE. Maternal/infant rehospitalization was more common; most marked in the early months postpartum. Close follow-up during these time periods is crucial to minimize adverse outcomes.

Purpose: The majority of adolescent and young adult (AYA) cancer survivors do not receive recommended health care surveillance after therapy. We used cross-sectional survey data to evaluate the impact of income, education, marital status, and insurance on health care adherence among AYA survivors. Methods: Eligible survivors were 18-39 years at diagnosis with invasive malignancy, 1-5 years from therapy completion. Online surveys assessed sociodemographic factors and self-report of completion of recommended health care services. Diagnosis and treatment data were abstracted from medical records. Multivariable logistic regression calculated odds ratios (ORs) and 95% confidence intervals (CIs) for adherence in relation to socioeconomic status and support. Results: Of 344 participants, 36% were adherent to at least 80% of recommendations. Adherence varied by cancer type: 34% for breast cancer, 52% for leukemia/lymphoma, 23% for other tumors. Adherence rates were similar among White, Asian, and Hispanic/Latinx patients. Lower adherence was associated with lower education (OR: 0.43; 95% CI: 0.23-0.80 for <4-year college degree) and lower annual income (OR: 0.51; 95% CI: 0.28-0.95 for $41,000-$80,000; OR: 0.40; 95% CI: 0.19-0.86 for ≤$40,000). Adherence decreased with decreasing income levels among those who were 1 to less than 3 years after diagnosis (OR: 0.25; 95% CI: 0.07-0.93 for $81,000-$120,000; OR: 0.24; 95% CI: 0.07-0.84 for $41,000-$80,000; OR: 0.13; 95% CI: 0.03-0.60 for ≤$40,000). Conclusion: Risk of nonadherence to health care guidelines was associated with lower income and lower education among AYA cancer survivors. Identification of these risks and related barriers to adherence in AYA survivors will inform interventions designed to meet needs of these high-risk groups, particularly during the first years after diagnosis. Trial Registration: NCT02192333.

6537 Background: Emerging evidence suggests mortality among children with cancer differs based on socioeconomic factors. The effects of residential location in relation to these factors are not well-characterized. We examined associations of rurality and neighborhood-level socioeconomic (SE) disadvantage with mortality in pediatric patients with cancer. Methods: We conducted a retrospective cohort study using Washington State (WA) Cancer Registry data (1992-2013) linked to state birth (1974-2013) and death records (1992-2013) to identify all children born in WA diagnosed with cancer < 20 years. We defined rural residence as patient addresses within 2010 census tract level rural-urban commuting area (RUCA) codes of ≥4.0 at diagnosis. Neighborhood-level socioeconomic disadvantage was determined using 2010 census block-group level Area Deprivation Index (ADI) quintiles normalized to WA. Patient addresses within the highest ADI quintile were categorized as having SE disadvantage. children in four mutually exclusive groups was compared using Kaplan-Meier analysis, pairwise log rank testing, and Cox proportional hazard ratios (HR): non-rural with SE disadvantage, rural without SE disadvantage, rural with SE disadvantage, and non-rural without SE disadvantage (). Models were adjusted for sex, race and ethnicity, age at diagnosis, birth year, and cancer type. Results: We identified 4,417 children for analysis. Median length of follow up among survivors was 5.0 years (inter-quartile range: 1.0-11.5). SE disadvantaged and 13% were rural. Pairwise log rank tests showed mortality differences among children living in rural, SE disadvantaged, or rural and SE disadvantaged neighborhoods when compared with children without either factor (individual p-values all < 0.005); no other differences were noted. Relative to children in non-rural areas without SE disadvantage, the mortality HR for those in non-rural areas with SE disadvantage was 1.68 (95% confidence intervals [CI] 1.37-2.07). The HR for children in rural areas without SE disadvantage was 1.59 (95% CI 1.19-2.12). The HR for children in rural areas with SE disadvantage was 1.56 (95% CI 1.20-2.03). In sub-analyses, associations for rurality and SE disadvantage remained significant for leukemia mortality, but CNS and solid tumor mortality was only associated with SE disadvantage (but not rural) status. Acute lymphoblastic leukemia mortality was associated with rural (but not SE disadvantage) status. Conclusions: Children with cancer living in socioeconomically disadvantaged and/or rural neighborhoods at diagnosis had higher mortality relative to those in non-rural areas with lower neighborhood deprivation. Associations varied by disease type. The individual effects of SE disadvantage and rurality suggest that interventions should be designed to target both factors.

Objective: Parental serious mental illness (SMI) is associated with childhood injury. This study investigated whether child injury risk differs according to which parent is affected, SMI diagnosis, or timing of SMI onset.Methods: This cohort study included 1,999,322 singletons born in 2004-2014 identified from the national Taiwanese registries. General estimating equation Poisson models were used to estimate incidence rate ratios (IRRs) of injury events and hospitalizations before the age of 5 years among children according to which parent was affected, SMI diagnosis (schizophrenia [ICD-9-CM codes: 295, 297, 298.3, 298.4, 298.9], bipolar disorder [296.00-296.16, 296.40-296.81, 296.89-296.99, 298.1, 648.4], or major depressive disorder [MDD; 296.20-296.36, 296.82, 298.0]), and timing of diagnosis (before or after childbirth, as a proxy of timing of onset). Data analysis was performed on data obtained from April 20, 2017, to May 6, 2020.Results: Relative to unexposed children, the IRRs of injury hospitalizations for children with two SMI-affected parents, maternal SMI only, and paternal SMI only were 1.85 (95% CI, 1.38-2.48), 1.58 (95% CI, 1.48-1.68), and 1.34 (95% CI, 1.23-1.46), respectively. The IRRs of injury hospitalizations for maternal schizophrenia, bipolar disorder, and MDD were 2.09 (95% CI, 1.82-2.40), 1.77 (95% CI, 1.56-2.00), and 1.38 (95% CI, 1.26-1.50), respectively. The IRRs for paternal schizophrenia, bipolar disorder, and MDD were 1.39 (95% CI, 1.20-1.60), 1.61 (95% CI, 1.39-1.87), and 1.19 (95% CI, 1.05-1.36), respectively. The magnitude of excess risk was similar for children whose parent(s) experienced SMI diagnosed before and after childbirth.Conclusions: We found children with two SMI-affected parents or at least one parent with schizophrenia or bipolar disorder to be at greatest risk of severe injury requiring hospitalization. These parents may benefit from extra parenting support and injury prevention coaching.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81‐0.96) or 7 to 12 months (OR 0.85, 0.79‐0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71‐0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63‐0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53‐0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B‐ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Objective: We compared the relative occurrence of selected pregnancy outcomes and postpartum rehos-pitalizations among women with and without epilepsy and their infants. Using linked vital-hospital dis-charge records of women with deliveries in Washington State 1987-2014, comparisons were made overall, by epilepsy type, and by time periods related to antiepileptic drug (AED) marketing changes.Methods: This population-based retrospective cohort study identified women with, and without epilepsy per diagnosis codes in the hospital discharge record from among all deliveries during 1987-2014 to examine maternal and infant outcomes, rehospitalization and mortality <2 years postpartum. Relative risks (RRs) and 95 % confidence intervals (CI) overall, and by epilepsy type were calculated using Poisson regression. We assessed the validity of epilepsy identification based on diagnosis codes by con-ducting a medical chart review for a sample of women.Results: Women with epilepsy had increased risks of preeclampsia (RR 1.23; 95 % CI 1.08-1.41) and ges-tational diabetes (RR 1.18; 95 % CI 1.02-1.36). Their infants had increased malformation (RR 1.23; 95 % C: 1.08-1.42) and small for gestational age (SGA, RR 1.39; 95 % CI 1.25-1.54) risks, and were nearly three times as likely to not be breastfed. Affected mothers (RR 5.25; 95 % CI 2.46-11.23) and their infants (RR 1.64, 95 % CI 1.41-1.89) required more ICU admissions during the delivery hospitalizations, and more postpartum rehospitalization, with greatest risk in the first six months. Maternal mortality < 2 years after delivery was increased (RR 7.11; 95 % CI 2.47-20.49). Increased risks were observed for all epilepsy sub-types for nearly all outcomes examined. Risks of preterm delivery and low birthweight increased over time (p <.05). Suggestive, but not statistically significant temporal decreases in risks of gestational dia-betes and malformations and increased risk of preterm labor were noted. We observed high sensitivity of diagnosis codes for identifying pregnant women with epilepsy.Conclusion: These population-based results emphasize the need for frequent postpartum monitoring of women with epilepsy. Increases in risks of low birthweight and preterm delivery over time are of con-cern. Possible temporal changes in other outcomes warrant further investigation.(c) 2022 Elsevier Inc. All rights reserved.

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early‐onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan‐tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non‐DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196–292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging‐related traits in DS.

Background: Down syndrome (DS) is associated with an up to 30-fold increased risk of B-cell acute lymphoblastic leukemia (ALL), and DS-ALL patients have worse overall survival and increased long-term treatment-related health conditions compared with non-DS ALL patients. In a recent genome-wide association study of DS-ALL, established ALL genetic risk loci were associated with DS-ALL, with several single nucleotide polymorphisms (SNPs) conferring a larger effect on ALL risk in the context of DS than in euploidy. We performed an epigenome-wide association study (EWAS) to elucidate whether epigenetic differences at birth are associated with risk of subsequent DS-ALL.

Importance:Cancer outcomes are relatively poor in adults who belong to minoritized racial and ethnic groups. Survival and long-term outcomes by race and ethnicity in individuals with childhood cancers are less studied.Objective:To evaluate survival and hospitalization among American Indian and Alaska Native, Asian, Black, and Hispanic children compared with non-Hispanic White children with cancer.Design, Setting, and Participants:This cohort study evaluated all individuals born in Washington State who were younger than 20 years (hereafter referred to as children) and had been diagnosed with cancer during 1987 to 2012, with follow-up ranging from 1 to 27 years. The data subset was built in 2019, and statistical analyses were completed in January 2022.Exposures:Race and ethnicity.Main Outcomes and Measures:Mortality and hospitalization events for all other racial and ethnic groups relative to non-Hispanic White children estimated by Cox proportional hazards regressions for the first 5 years after diagnosis and among cancer survivors 5 or more years after diagnosis.Results:A total of 4222 children (mean [SD] age, 8.4 [6.4] years; 2199 [52.1%] male; 113 American Indian and Alaska Native [2.7%], 311 Asian [7.4%], 196 Black [4.6%], 387 Hispanic [9.2%], and 3215 non-Hispanic White [76.1%]) with cancer diagnosed at younger than 20 years during 1987 to 2012 were included. Mortality was similar across all groups. Compared with non-Hispanic White survivors at less than 5 years after diagnosis, there were no greatly increased hazard ratios (HRs) for hospitalization. Among survivors at 5 or more years after diagnosis, hospitalization HRs were 1.7 (95% CI, 1.0-3.0) for American Indian and Alaska Native survivors and 1.5 (95% CI, 0.9-2.4) for Black survivors. Significantly increased HRs among Hispanic children were observed for infection-related (HR, 1.4; 95% CI, 1.2-1.6), endocrine-related (HR, 1.3; 95% CI, 1.1-1.6), hematologic-related (HR, 1.3; 95% CI, 1.1-1.5), respiratory-related (HR, 1.3; 95% CI, 1.0-1.5), and digestive-related (HR, 1.2; 95% CI, 1.0-1.5) conditions. American Indian and Alaskan Native children had increased HRs for infection-related (HR, 2.3; 95% CI, 1.2-4.5), hematologic-related (HR, 3.0; 95% CI, 1.4-6.5), and digestive-related (HR, 2.6; 95% CI, 1.3-5.4) conditions. Both American Indian and Alaska Native (HR, 3.6; 95% CI, 1.4-9.0) and Black (HR, 2.5; 95% CI, 1.2-5.5) children had increased mental health-related hospitalizations and death.Conclusions and Relevance:In this cohort study, disproportionately increased long-term risks of hospitalization for physical and mental conditions may have contributed to worse outcomes by race. A key component to bridging the morbidity gap by race is improved understanding of reasons for greater cause-specific hospitalizations in some groups, with development of culturally appropriate intervention strategies.

The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been reported to be associated with survival after chronic disease diagnoses, including lung cancer. We hypothesized that the inflammatory profile reflected by pre-diagnosis NLR, rather than the well-studied pre-treatment NLR at diagnosis, may be associated with increased mortality after lung cancer is diagnosed in high-risk heavy smokers. We examined associations between pre-diagnosis methylation-derived NLR (mdNLR) and lung cancer-specific and all-cause mortality in 279 non-small lung cancer (NSCLC) and 81 small cell lung cancer (SCLC) cases from the β-Carotene and Retinol Efficacy Trial (CARET). Cox proportional hazards models were adjusted for age, sex, smoking status, pack years, and time between blood draw and diagnosis, and stratified by stage of disease. Models were run separately by histotype. Among SCLC cases, those with pre-diagnosis mdNLR in the highest quartile had 2.5-fold increased mortality compared to those in the lowest quartile. For each unit increase in pre-diagnosis mdNLR, we observed 22–23% increased mortality (SCLC-specific hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.02, 1.48; all-cause HR = 1.22, 95% CI 1.01, 1.46). SCLC associations were strongest for current smokers at blood draw (Interaction Ps = 0.03). Increasing mdNLR was not associated with mortality among NSCLC overall, nor within adenocarcinoma (N = 148) or squamous cell carcinoma (N = 115) case groups. Our findings suggest that increased mdNLR, representing a systemic inflammatory profile on average 4.5 years before a SCLC diagnosis, may be associated with mortality in heavy smokers who go on to develop SCLC but not NSCLC.

Antihypertensives are commonly prescribed medications and their effect on breast cancer recurrence and mortality is not clear, particularly among specific molecular subtypes of breast cancer: luminal, triple-negative (TN), and HER2-overexpressing (H2E). A population-based prospective cohort study of women aged 20–69 diagnosed with a first primary invasive breast cancer between 2004 and 2015 was conducted in the Seattle, Washington and Albuquerque, New Mexico greater metropolitan areas. Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality associated with hypertension and antihypertensives. In this sample of 2,383 luminal, 1,559 TN, and 615 H2E breast cancer patients, overall median age was 52 (interquartile range, 44–60). Hypertension and current use of antihypertensives were associated with increased risks of all-cause mortality in each subtype. Current use of angiotensin-converting enzyme inhibitors was associated with increased risks of both recurrence and breast cancer-specific mortality among luminal patients (HR: 2.5; 95% CI: 1.5, 4.3 and HR: 1.9; 95% CI: 1.2, 3.0, respectively). Among H2E patients, current use of calcium channel blockers was associated with an increased risk of breast cancer-specific mortality (HR: 1.8; 95% CI: 0.6, 5.4). Our findings suggest that some antihypertensive medications may be associated with adverse breast cancer outcomes among women with certain molecular subtypes. Additional studies are needed to confirm these findings.