Publications by authors named "Cara L Carty"

61 Publications

Substance use and mental health in pregnant women during the COVID-19 pandemic.

J Reprod Infant Psychol 2021 Apr 17:1-14. Epub 2021 Apr 17.

Analytics and PsychoPharmacology Laboratory (APPL), Washington State University, Spokane, WA, U.S.A.

: We examined the prevalence of substance use as a coping mechanism and identified relationships between maternal mental health over time and use of substances to cope during the Coronavirus Disease 2019 (COVID-19) pandemic among pregnant women in the U.S.A.: Self-reported repeated measures from 83 pregnant women were collected online in April 2020 and May 2020. Women retrospectively reported their mental/emotional health before the pandemic, as well as depression, stress, and substance use as a result of the pandemic at both time points. Linear regression measured cross-sectional and longitudinal associations between mental health and substance use.: Pre-COVID-19 reports of poorer mental/emotional health ( = 0.46) were significantly (.05) associated with number of substances used to cope with the pandemic. Elevated stress ( = 0.35) and depressive symptoms ( = 0.27) and poorer mental/emotional health ( = 0.14) in April were also significantly related to higher numbers of substances used in May (.05).: Pregnant women's psychological well-being may be a readily measured indicator substance use risk during crises such as the COVID-19 pandemic. Interventions addressing increased stress and depression may also mitigate the emergence of greater substance use among pregnant women .
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http://dx.doi.org/10.1080/02646838.2021.1916815DOI Listing
April 2021

Stressors, coping, and resources needed during the COVID-19 pandemic in a sample of perinatal women.

BMC Pregnancy Childbirth 2021 Mar 1;21(1):171. Epub 2021 Mar 1.

Department of Psychology, Washington State University, Pullman, WA, USA.

Background: Psychological stress and coping experienced during pregnancy can have important effects on maternal and infant health, which can also vary by race, ethnicity, and socioeconomic status. Therefore, we assessed stressors, coping behaviors, and resources needed in relation to the COVID-19 pandemic in a sample of 162 perinatal (125 pregnant and 37 postpartum) women in the United States.

Methods: A mixed-methods study captured quantitative responses regarding stressors and coping, along with qualitative responses to open-ended questions regarding stress and resources needed during the COVID-19 pandemic. Logistic and linear regression models were used to analyze differences between pregnant and postpartum participants, as well as differences across key demographic variables. Qualitative content analysis was used to analyze open-ended questions.

Results: During the COVID-pandemic, food scarcity and shelter-in-place restrictions made it difficult for pregnant women to find healthy foods. Participants also reported missing prenatal appointments, though many reported using telemedicine to obtain these services. Financial issues were prevalent in our sample and participants had difficulty obtaining childcare. After controlling for demographic variables, pregnant women were less likely to engage in healthy stress-coping behaviors than postpartum women. Lastly, we were able to detect signals of increased stressors induced by the COVID-19 pandemic, and less social support, in perinatal women of racial and ethnic minority, and lower-income status. Qualitative results support our survey findings as participants expressed concerns about their baby contracting COVID-19 while in the hospital, significant others missing the delivery or key obstetric appointments, and wanting support from friends, family, and birthing classes. Financial resources, COVID-19 information and research as it relates to maternal-infant health outcomes, access to safe healthcare, and access to baby supplies (formula, diapers, etc.) emerged as the primary resources needed by participants.

Conclusions: To better support perinatal women's mental health during the COVID-19 pandemic, healthcare providers should engage in conversations regarding access to resources needed to care for newborns, refer patients to counseling services (which can be delivered online/via telephone) and virtual support groups, and consistently screen pregnant women for stressors.
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http://dx.doi.org/10.1186/s12884-021-03665-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920400PMC
March 2021

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA Netw Open 2021 01 4;4(1):e2030435. Epub 2021 Jan 4.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

Design, Setting, And Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes And Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions And Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786247PMC
January 2021

Risk Factors for Alzheimer's Disease and Related Dementia Diagnoses in American Indians.

Ethn Dis 2020 24;30(4):671-680. Epub 2020 Sep 24.

IREACH, Washington State University, Seattle, WA.

The burden of Alzheimer's disease and related dementias (ADRD) has increased substantially in the United States, particularly in health disparity populations. Little is known about the epidemiology of ADRD in American Indian (AI) adults, although they have a high prevalence of ADRD risk factors including hypertension, diabetes, obesity, and smoking. Using electronic health records from a large health care organization during 2016-18, we describe characteristics of AI patients aged ≥55 years with and without an ADRD diagnosis, assess ADRD risk factors and contrast findings with results from age- and sex-matched non-Hispanic White (NHW) patients. To identify factors associated with ADRD diagnoses, we estimated population-averaged prevalence rate ratios to approximate relative risk (RR) using generalized estimating equations models adjusted for age, sex, and marital and rural residency status. The age-adjusted prevalence of ADRD diagnosis was 6.6% of AI patients, compared with 4.4% in NHW patients. Patient age and diagnosis of hypertension, depression, hyperlipidemia, or diabetes were significantly associated with higher risk of ADRD diagnosis in AIs (RR range: 1.1-2.8) whereas female sex or being married/having a partner were associated with lower risk of ADRD diagnosis (each RR=.7). ADRD risk factors were generally similar between AI and NHW patients, except for sex and marital status. However, the adjusted risk of ADRD was approximately 49% higher in AI patients. To our knowledge, our study is the first to examine ADRD diagnoses and comorbidities in AIs across a large geographical region in southwest United States. Future efforts to confirm our findings in diverse AI communities are warranted.
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http://dx.doi.org/10.18865/ed.30.4.671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518528PMC
April 2021

Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

Stroke 2020 08 22;51(8):2454-2463. Epub 2020 Jul 22.

Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.).

Background And Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.

Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.

Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the gene that reached genome-wide significance (=4.62×10) and an additional 29 variants with suggestive evidence of association (<1×10), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction value of 2.08×10 (0.05/24 unique loci), we were able to validate associations at the locus in both SiGN (=8.18×10) and METASTROKE (=1.72×10) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the and genes represent potential novel ischemic stroke loci.

Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
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http://dx.doi.org/10.1161/STROKEAHA.120.029123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387190PMC
August 2020

Parental Depression Symptoms at Neonatal Intensive Care Unit Discharge and Associated Risk Factors.

J Pediatr 2020 12 15;227:163-169.e1. Epub 2020 Jul 15.

Center for Translational Science, Children's Research Institute, Children's National Hospital, Washington, DC; Division of General and Community Pediatrics, Children's National Hospital, Washington, DC.

Objective: To investigate the prevalence and risk factors associated with parental depressive symptoms at neonatal intensive care unit (NICU) discharge and determine the relationships among depressive symptoms, stress, and social support.

Study Design: Parents participating in the Giving Parents Support trial (n = 300) were surveyed before NICU discharge. Depressive symptoms, stress, and social support were assessed using the Center for Epidemiological Studies Depression Scale (CESD-10), Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU), Perceived Stress Scale (PSS-10), and Multidimensional Scale of Perceived Social Support (MSPSS). Regression analyses examined relationships among depressive symptoms, stress, social support, and parent/infant factors.

Results: At NICU discharge, 45% of parents reported depressive symptoms and 43% reported elevated perceived stress. Increased odds of elevated depressive symptoms were associated with older gestational age (P = .02), female infant (P = .02), and longer length of stay (P = .045). Odds of depression were 7.87 (95% CI, 2.15-28.75) for parents of infants with gestational age ≥37 weeks compared with gestational age <28 weeks. Parental NICU stress was higher in younger parents (P < .01). Depressive symptoms were positively associated with parental stress. Each 1-point increase in PSS:NICU score was associated with a 2.1-point (95% CI, 1.6-2.9; P < .001) increase in CESD-10 score. Social support was inversely associated with depressive symptoms.

Conclusion: The prevalence of depressive symptoms in parents at NICU discharge was high, even among parents of term infants. Older gestational age, greater parental stress, and lower levels of social support were strong correlates of depressive symptoms. Strategies to support parents, including depression screening, stress reduction strategies, and mental health referrals, are needed.
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http://dx.doi.org/10.1016/j.jpeds.2020.07.040DOI Listing
December 2020

Lifestyle Risk Factors and Findings on Brain Magnetic Resonance Imaging of Older Adult American Indians: The Strong Heart Study.

Neuroepidemiology 2019 4;53(3-4):162-168. Epub 2019 Jun 4.

Partnerships for Native Health, Washington State University, Pullman, Washington, USA.

Background: Clinical stroke is prevalent in American Indians, but the lifestyle risk factors for vascular brain injury have not been well-studied in this population. The purpose of this study was to correlate brain magnetic resonance imaging (MRI) findings with obesity, alcohol use, and smoking behaviors in elderly American Indians from the Strong Heart Study.

Methods: Cranial MRI scans (n = 789) were analyzed for dichotomous measures of infarcts, hemorrhages, white matter hyperintensities (WMH), and cerebral atrophy and continuous measures of total brain, WMH, and hippocampal volume. Poisson regression was used to estimate prevalence ratios, and linear regression was used to estimate measures of association for continuous outcomes. Models were adjusted for the risk factors of interest as well as age, sex, study site, income, education, hypertension, diabetes, and low-density lipoprotein cholesterol.

Results: Smoking was associated with increased hippocampal atrophy (p = 0.002) and increased prevalence of sulcal widening (p < 0.001). Relative to nonsmokers, smokers with more than 25 pack-years of smoking had a 27% (95% CI 7-47%) increased prevalence of high-grade sulci, p = 0.005. Body mass index was inversely associated with prevalence of nonlacunar infarcts and sulcal widening (all p = 0.004). Alcohol use was not significantly associated with any of the measured MRI findings.

Conclusions: This study found similar associations between smoking and vascular brain injury among American Indians, as seen in other populations. In particular, these findings support the role of smoking as a key correlate for cerebral atrophy.
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http://dx.doi.org/10.1159/000501181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986811PMC
June 2020

A Cross-Sectional Analysis of Telomere Length and Sleep in the Women's Health Initiative.

Am J Epidemiol 2019 09;188(9):1616-1626

Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, New York.

Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women's Health Initiative in 1993-1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted β = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted β = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.
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http://dx.doi.org/10.1093/aje/kwz134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736371PMC
September 2019

Vascular Risk Factors and Findings on Brain MRI of Elderly Adult American Indians: The Strong Heart Study.

Neuroepidemiology 2019 24;52(3-4):173-180. Epub 2019 Jan 24.

Partnerships for Native Health, Washington State University, Seattle, Washington, USA.

Background: Clinical stroke is prevalent in American Indians, but the risk factors for cerebrovascular pathology have not been well-studied in this population. The purpose of this study was to correlate abnormalities on brain magnetic resonance imaging (MRI) with clinical risk factors in a cohort of elderly American Indians.

Methods: Brain MRI scans from 789 participants of the Strong Heart Study were analyzed for infarcts, hemorrhage, white matter disease, and measures of cerebral atrophy including ventricular and sulcal grade and total brain volume. Clinical risk factors included measures of hypertension, diabetes, and high levels of low-density lipoprotein (LDL) cholesterol. Regression models adjusted for potential confounders were used to estimate associations between risk factors and brain MRI outcomes.

Results: -Hypertension was associated with the presence of infarcts (p = 0.001), ventricle enlargement (p = 0.01), and increased white matter hyperintensity volume (p = 0.01). Diabetes was associated with increased prevalence of cerebral atrophy (p < 0.001), ventricular enlargement (p = 0.001), and sulcal widening (p = 0.001). High LDL was not significantly associated with any of the measured cranial imaging outcomes.

Conclusions: This study found risk factors for cerebrovascular disease in American Indians similar to those seen in other populations and provides additional evidence for the important roles of hypertension and diabetes in promoting cerebral infarcts and brain atrophy, respectively.
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http://dx.doi.org/10.1159/000496343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986809PMC
December 2019

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis.

PLoS One 2018 25;13(7):e0200486. Epub 2018 Jul 25.

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America.

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059436PMC
January 2019

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Hum Mol Genet 2018 08;27(16):2940-2953

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.
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http://dx.doi.org/10.1093/hmg/ddy211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077792PMC
August 2018

The Giving Parents Support Study: A randomized clinical trial of a parent navigator intervention to improve outcomes after neonatal intensive care unit discharge.

Contemp Clin Trials 2018 07 5;70:117-134. Epub 2018 May 5.

Center for Translational Science, Children's Research Institute, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA; Goldberg Center for Community Pediatric Health, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA. Electronic address:

Parents of infants hospitalized in a neonatal intensive care unit (NICU) experience increased anxiety and stress, which may persist after discharge. The rationale and design of a randomized clinical trial assessing the impact of a 1-year, post-discharge, peer support intervention (parent navigation) on parental mental health and infant health care utilization is described. Qualitative methods guided the adaptation of an existing parent support program to target emotional and resource-related needs of NICU families. Approximately 300 parent-infant dyads were enrolled at discharge and randomized to either receive a care notebook (control group) or a parent navigator and a care notebook (intervention group). We aim to determine if the parent navigator intervention: 1) increases self-efficacy and decreases stress in parents, 2) decreases overall levels of anxiety and depression in parents, 3) decreases infant hospitalizations and emergency department visits, and 4) increases adherence to infant vaccination recommendations during 1 year of follow-up. Standardized, self-reported psychological scales to assess parent depression, anxiety, self-efficacy and social support were administered at baseline (NICU discharge) and at 1-week, 1-, 3-, 6- and 12-month intervals. Infant immunization status and health care utilization during the study period were also assessed. This paper reviews challenges and successes during implementation. If this intervention improves outcomes, NICUs may choose to provide similar parent navigation services for infants and families transitioning from the NICU to home. This study was registered with ClinicalTrials.gov (NCT02643472) on December 31, 2015.
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http://dx.doi.org/10.1016/j.cct.2018.05.004DOI Listing
July 2018

Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis.

JAMA Neurol 2018 07;75(7):802-807

Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington.

Importance: African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear.

Objective: To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans.

Design, Setting, And Participants: This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women's Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017.

Interventions Or Exposures: Participants' SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation.

Main Outcomes And Measures: Incident ischemic stroke.

Results: This meta-analysis included 19 464 African American individuals (1520 with SCT, 17 944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar.

Conclusions And Relevance: Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.
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http://dx.doi.org/10.1001/jamaneurol.2018.0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145767PMC
July 2018

Combination of indoor residual spraying with long-lasting insecticide-treated nets for malaria control in Zambezia, Mozambique: a cluster randomised trial and cost-effectiveness study protocol.

BMJ Glob Health 2018 30;3(1):e000610. Epub 2018 Jan 30.

Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.

Background: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions.

Methods: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes.

Discussion: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies.

Trial Registration Number: NCT02910934.
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http://dx.doi.org/10.1136/bmjgh-2017-000610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859815PMC
January 2018

A multinational study on motor function in early-onset FSHD.

Neurology 2018 04 14;90(15):e1333-e1338. Epub 2018 Mar 14.

From the University of Calgary (J.K.M.), Alberta Children's Hospital, Canada; Children's National Medical Center (J.F., M.B.J., C.L.C., L.M., M.T., A.C., Y.-W.C.), Washington, DC; Stanford University (T.D.), CA; Royal Children's Hospital (K.C., K.d.V., M.M.R.), Melbourne, Australia; Newcastle Upon Tyne Hospitals (M.G.), UK; University of Pittsburgh (P.R.C.) and the Department of Veteran Affairs Medical Center, PA; Children's Hospital at Westmead (R.W.), Sydney, Australia; Duke Medical Center (E.S.), Durham, NC; Washington University (A.M.C.), St. Louis, MO; University of California at Davis Medical Center (C.M.M.), Sacramento; University of Minnesota (P.K.), Minneapolis; Gothenburg University (M.T.), Queen Silvia Children's Hospital, Sweden; Carolinas Medical Center (A.H.), Charlotte, NC; and Therapeutic Research in Neuromuscular Disorders Solutions (L.P.M.), LLC, Kensington, MD.

Objectives: To investigate motor function associations with age, sex, and repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age.

Methods: We collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and repeats.

Results: Among 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs ( = 0.003). When adjusted for enrollment age, sex, and repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores ( < 0.05).

Conclusion: Significant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.
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http://dx.doi.org/10.1212/WNL.0000000000005297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894929PMC
April 2018

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Nat Genet 2018 04 12;50(4):524-537. Epub 2018 Mar 12.

Institute of Cardiovascular Research, Royal Holloway University of London, London, UK, and Ashford and St Peters Hospital, Surrey, UK.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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http://dx.doi.org/10.1038/s41588-018-0058-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968830PMC
April 2018

Leukocyte telomere length, T cell composition and DNA methylation age.

Aging (Albany NY) 2017 09;9(9):1983-1995

Center of Development and Aging, New Jersey Medical School, Rutgers State University of New Jersey, Newark, NJ 07103, USA.

Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8 T cells, memory CD8 T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (=-0.16, =3.1x10). This finding was replicated in the FHS (=-0.09, =6.5x10) and the BHS (=-0.07, =3.8x 10). LTL was also inversely related to proportions of memory CD8 T cells (=4.04x10) and positively related to proportions of naive CD8 T cells (=3.57x10). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8 T cells and less naive CD8 T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.
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http://dx.doi.org/10.18632/aging.101293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636670PMC
September 2017

Leisure-time physical activity and leukocyte telomere length among older women.

Exp Gerontol 2017 09 25;95:141-147. Epub 2017 May 25.

Division of Epidemiology, Family Medicine and Public Health, University of California, San Diego School of Medicine, 9500 Gilman Drive #0725, La Jolla, CA 92093, USA.

Background: Shortened leukocyte telomere length (LTL), a purported marker of cellular aging, is associated with morbidity and mortality. However, the association of physical activity, a modifiable lifestyle behavior, with LTL has not been adequately studied among older adults.

Methods: In this cross-sectional study, we examined associations of various intensity levels of leisure-time physical activity with LTL among 1476 older white and African American women from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health study. Self-reported physical activity was assessed by questionnaire, and LTL was measured by Southern blot. The association between physical activity and LTL was evaluated using multiple linear regression models adjusted for demographic characteristics, lifestyle behaviors, and health-related variables.

Results: Women were on average aged 79.2 (standard deviation 6.7) years old. In the final model adjusted for age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was on average 110 (95% confidence interval, 20-190) base pairs longer among women in the highest (≥17.00MET-hours/week) compared with the lowest (<1.25MET-hours/week) level of total leisure-time physical activity (P for trend=0.02). Higher levels of moderate-to-vigorous physical activity (P for trend=0.04) and faster walking speed (P for trend=0.03) were also associated with longer LTL in the fully-adjusted models.

Conclusion: Older women participating in greater amounts of total leisure-time physical activity and moderate-to-vigorous physical activity had longer LTL.
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http://dx.doi.org/10.1016/j.exger.2017.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530759PMC
September 2017

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

Nat Genet 2017 Jul 22;49(7):1113-1119. Epub 2017 May 22.

Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.
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http://dx.doi.org/10.1038/ng.3874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555387PMC
July 2017

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci.

Hum Mol Genet 2016 12;25(24):5500-5512

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.
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http://dx.doi.org/10.1093/hmg/ddw358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721937PMC
December 2016

Association of Accelerometer-Measured Physical Activity With Leukocyte Telomere Length Among Older Women.

J Gerontol A Biol Sci Med Sci 2017 Oct;72(11):1532-1537

Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego School of Medicine, La Jolla.

Background: Previous studies on physical activity and telomere length have relied largely upon self-reported physical activity data, and few studies have examined older adults. The association of objectively measured physical activity with leukocyte telomere length (LTL) is currently unknown.

Methods: In this study, we examined cross-sectional associations between accelerometer-measured total, light, and moderate-to-vigorous physical activity (MVPA) and LTL, measured using Southern blot. The sample included 1,405 older (64-95 years old) white and African American women from the Women's Health Initiative. Multiple linear regression models adjusting for potential confounders were used to determine the association between accelerometer-measured physical activity and LTL.

Results: Overall, the mean (standard deviation) of total, light, and moderate-to-vigorous activity was 5.5 (1.6), 4.7 (1.3), and 0.8 (0.5) h/d, respectively. Adjusting for accelerometer wear time, age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was 80 (95% confidence interval: 9, 150) base pairs longer among women with ≥2.5 compared with <2.5 h/wk of MVPA. Light activity was not significantly associated with LTL. For total activity, the most physically active women had significantly longer LTL than the least active women after adjustment for demographic and lifestyle characteristics; however, findings were not significant after further adjustment for health-related factors.

Conclusions: Older women meeting current recommendations of ≥2.5 h/wk of MVPA, as assessed by accelerometer, had longer LTL. Additional studies using accelerometers in large, diverse cohorts of older women are needed to confirm and extend these findings.
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http://dx.doi.org/10.1093/gerona/glx037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861863PMC
October 2017

Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women.

Am J Epidemiol 2017 02;185(3):172-184

Few studies have assessed the association of sedentary time with leukocyte telomere length (LTL). In a cross-sectional study conducted in 2012-2013, we examined associations of accelerometer-measured and self-reported sedentary time with LTL in a sample of 1,481 older white and African-American women from the Women's Health Initiative and determined whether associations varied by level of moderate- to vigorous-intensity physical activity (MVPA). The association between sedentary time and LTL was evaluated using multiple linear regression models. Women were aged 79.2 (standard deviation, 6.7) years, on average. Self-reported sedentary time was not associated with LTL. In a model adjusting for demographic characteristics, lifestyle behaviors, and health-related factors, among women at or below the median level of accelerometer-measured MVPA, those in the highest quartile of accelerometer-measured sedentary time had significantly shorter LTL than those in the lowest quartile, with an average difference of 170 base pairs (95% confidence interval: 4, 340). Accelerometer-measured sedentary time was not associated with LTL in women above the median level of MVPA. Findings suggest that, on the basis of accelerometer measurements, higher sedentary time may be associated with shorter LTL among less physically active women.
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http://dx.doi.org/10.1093/aje/kww196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391715PMC
February 2017

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

Hum Mol Genet 2016 10 29;25(19):4350-4368. Epub 2016 Aug 29.

Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
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http://dx.doi.org/10.1093/hmg/ddw284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291202PMC
October 2016

Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans.

PLoS One 2016 13;11(10):e0164132. Epub 2016 Oct 13.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10-9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans-populations that are understudied for hypertension genetic risk factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164132PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063457PMC
May 2017

DNA methylation-based measures of biological age: meta-analysis predicting time to death.

Aging (Albany NY) 2016 09;8(9):1844-1865

Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10, independent of chronological age, even after adjusting for additional risk factors (p<5.4x10, and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
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http://dx.doi.org/10.18632/aging.101020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076441PMC
September 2016

Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.

PLoS One 2016 7;11(3):e0144997. Epub 2016 Mar 7.

Departments of Cardiology and Epidemiology, Toulouse University Hospital, Toulouse, France.

Background: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

Methods: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

Results: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

Conclusions: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780701PMC
July 2016

Leukocyte Telomere Length and Risks of Incident Coronary Heart Disease and Mortality in a Racially Diverse Population of Postmenopausal Women.

Arterioscler Thromb Vasc Biol 2015 Oct 6;35(10):2225-31. Epub 2015 Aug 6.

From the Division of Biostatistics and Study Methodology, Center for Translational Science, George Washington University and Children's National Medical Center, Washington, DC (C.L.C.); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (C.K., J.L., M.H., A.P.R.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.A.); Division of Cancer Epidemiology and Prevention, Northwestern University Feinberg School of Medicine, Chicago, IL (L.H.); Kaiser Permanente Division of Research, Oakland, CA (C.H.K.); Department of Epidemiology, University of California, San Diego (A.Z.L.); Center of Development and Aging, New Jersey Medical School, Rutgers State University of New Jersey, Newark (M.K., A.A.); and Department of Epidemiology, University of Washington, Seattle (A.P.R.).

Objective: Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality among AfAm.

Approach And Results: Using a case-cohort design, 1525 postmenopausal women (667 AfAm and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas AfAm experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in AfAm. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in AfAm.

Conclusions: As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and AfAm postmenopausal women.
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http://dx.doi.org/10.1161/ATVBAHA.115.305838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713196PMC
October 2015

Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk: A Secondary Analysis of the Women's Health Initiative Randomized Clinical Trials.

JAMA Oncol 2015 Aug;1(5):611-21

Division of Public Health Sciences, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Importance: More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer.

Objective: To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women's Health Initiative (WHI) clinical trials.

Design, Setting, And Participants: The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67 142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed.

Main Outcomes And Measures: Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators.

Results: Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2 plus 3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor-positive and progesterone receptor-positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor-negative cancers. Obesity grade 2 plus 3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P = .02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P = .06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P = .05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P < .001). Women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period had an increased breast cancer risk (HR, 1.36; 95% CI, 1.1-1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy, and the direction of association across BMI categories was similar for never, past, and current hormone therapy use.

Conclusions And Relevance: Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention.

Trial Registration: clinicaltrials.gov Identifier: NCT00000611.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070941PMC
http://dx.doi.org/10.1001/jamaoncol.2015.1546DOI Listing
August 2015
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