Untargeted serum metabolomic profiles and breast density in young women.

PURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

Adverse pregnancy outcomes and risk of type 2 diabetes in postmenopausal women.

BACKGROUND: Although gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established. OBJECTIVE: This study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women. STUDY DESIGN: The Women's Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with medication from baseline (1993-1998) to March 2021. This study used logistic regression to examine the associations of any and individual adverse pregnancy outcomes with diabetes mellitus. Stratified analyses were performed to assess effect modification by body mass index, race and ethnicity, education, parity, breastfeeding, and age at first birth. RESULTS: This analysis included 49,717 women without a history of diabetes mellitus at enrollment who had a least 1 pregnancy and responded to the questionnaire about adverse pregnancy outcomes. After adjusting for body mass index, demographic, lifestyle, and reproductive factors, gestational diabetes mellitus (odds ratio, 2.26; 95% confidence interval, 1.94-2.63), high birthweight (odds ratio, 1.30; 95% confidence interval, 1.18-1.44), and hypertensive disorders of pregnancy (odds ratio, 1.18; 95% confidence interval, 1.08-1.30) were independently associated with higher odds of type 2 diabetes mellitus, whereas preterm birth and low birthweight were not associated with diabetes mellitus risk. A history of ≥2 adverse pregnancy outcomes was associated with higher odds of type 2 diabetes mellitus (odds ratio, 1.55; 95% confidence interval, 1.28-1.88). This study further observed higher odds of type 2 diabetes mellitus (odds ratio, 3.69; 95% confidence interval, 2.38-5.70) among women with a history of both gestational diabetes mellitus and hypertensive disorders of pregnancy than those without any adverse pregnancy outcomes. CONCLUSION: Postmenopausal women with a history of gestational diabetes mellitus, those delivering high-birthweight infants, or those with hypertensive disorders of pregnancy are at risk of future type 2 diabetes mellitus. In addition, women with ≥2 conditions had an augmented risk and might be prioritized for screening and prevention efforts for type 2 diabetes mellitus.

Childhood adiposity, serum metabolites and breast density in young women.

BACKGROUND: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density. METHODS: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation. RESULTS: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV. CONCLUSIONS: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

The relationship between sleep and weight change among women diagnosed with breast cancer participating in the Women's Health Initiative.

PURPOSE: Short and long sleep duration and poor sleep quality are risk factors for weight gain and cancer mortality. The purpose of this study is to investigate the relationship between sleep and weight change among postmenopausal breast cancer survivors. METHODS: Women participating in the Women's Health Initiative who were diagnosed with incident breast cancer between year one and year three were included. Self-reported sleep duration was categorized as ≤ 5 h (short), 6 h, 7-8 h (optimal), and ≥ 9 h (long). Self-reported sleep quality was categorized as poor, average, and above average. Post-diagnosis weight change was the difference of weight closest to, but preceding diagnosis, and year 3 weight. We used linear regression to evaluate sleep duration and sleep quality associations with post-diagnosis weight change adjusted for potential confounders. RESULTS: Among 1156 participants, 63% were weight stable after diagnosis; average weight gain post cancer diagnosis was 3.2 kg. Six percent of women reported sleeping ≤ 5 h, 26% reported 6 h, 64% reported 7-8 h, and 4% reported ≥ 9 h. There were no differences in adjusted estimates of weight change among participants with short duration (0.37 kg; 95% CI - 0.88, 1.63), or long duration (- 0.56 kg; 95% CI - 2.03, 0.90) compared to optimal duration, nor was there a difference among poor quality (- 0.51 kg; 95% CI - 1.42, 0.41) compared to above average quality. CONCLUSION: Among postmenopausal breast cancer survivors, sleep duration and quality were not associated with weight change after breast cancer diagnosis. Future studies should consider capturing change in adiposity and to expand beyond self-reported sleep.

Screening for Prediabetes and Type 2 Diabetes in Children and Adolescents: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Of youths diagnosed with type 2 diabetes, many develop microvascular complications by young adulthood. Objective: To review the evidence on benefits and harms of screening children and adolescents for prediabetes and type 2 diabetes to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through May 3, 2021; references; experts; literature surveillance through July 22, 2022. Study Selection: English-language controlled studies evaluating screening or interventions for prediabetes or type 2 diabetes that was screen detected or recently diagnosed. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings. Main Outcomes and Measures: Mortality, cardiovascular morbidity, diabetes-related morbidity, development of diabetes, quality of life, and harms. Results: This review included 8 publications (856 participants; mean age, 14 years [range, 10-17 years]). Of those, 6 were from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. No eligible studies directly evaluated the benefits or harms of screening. One randomized clinical trial (RCT) (TODAY; n = 699 adolescents with obesity; mean age, 14 years) comparing metformin, metformin plus rosiglitazone, and metformin plus lifestyle intervention reported that 2 youths with recently diagnosed diabetes developed kidney impairment (0 vs 1 vs 1, respectively; P > .99) and 11 developed diabetic ketoacidosis (5 vs 3 vs 3, respectively; P = .70). One RCT of 75 adolescents (mean age, 13 years) with obesity with prediabetes compared an intensive lifestyle intervention with standard care and reported that no participants in either group developed diabetes, although follow-up was only 6 months. Regarding harms of interventions, 2 RCTs assessing different comparisons enrolled youths with recently diagnosed diabetes. Major hypoglycemic events were reported by less than 1% of participants. Minor hypoglycemic events were more common among youths treated with metformin plus rosiglitazone than among those treated with metformin or metformin plus lifestyle intervention in TODAY (8.2% vs 4.3% vs 3.4%, P = .05). In 1 study, gastrointestinal adverse events were more commonly reported by those taking metformin than by those taking placebo (abdominal pain: 25% vs 12%; nausea/vomiting: 17% vs 10%; P not reported). Conclusions and Relevance: No eligible studies directly evaluated the benefits or harms of screening for prediabetes and type 2 diabetes in children and adolescents. For youths with prediabetes or recently diagnosed (not screen-detected) diabetes, the only eligible trials reported few health outcomes and found no difference between groups, although evidence was limited by substantial imprecision and a duration of follow-up likely insufficient to assess health outcomes.

Weight loss prior to pregnancy and subsequent gestational weight gain: Prepare, a randomized clinical trial.

BACKGROUND: Women with elevated body mass index are encouraged to lose weight before pregnancy, but no trials have tested the effects of prepregnancy weight loss on health outcomes. OBJECTIVE: This study aimed to determine whether prepregnancy weight loss reduces gestational weight gain and improves pregnancy outcomes. STUDY DESIGN: Pragmatic randomized clinical trial was conducted between May 2015 and October 2019 at Kaiser Permanente Northwest, an integrated health system. Data collection was blind to condition assignment. Eligible participants were women aged 18 to 40 years with a body mass index of ≥27 kg/m2 who were planning pregnancy within 2 years. Recruitment contacts were sent to 27,665 health system members who met age and body mass index criteria; 329 women attended screening visits, and 326 were randomized. They were randomized to either a behavioral weight loss intervention or usual care control. The intervention consisted of health coaching phone sessions weekly for 6 months and then monthly for 18 months or until end of pregnancy. We used logistic regression to examine the a priori primary hypothesis that participants in the intervention would be less likely to exceed National Academy of Medicine guidelines for gestational weight gain during each trimester and overall. Secondary and exploratory outcomes included absolute weight gain before and during pregnancy and perinatal and newborn outcomes. RESULTS: Of the 326 participants, 169 had singleton pregnancies lasting ≥14 weeks (analytical cohort: intervention, 89; control, 80). At baseline, mean age was 31.3±3.5 years, and body mass index was 34.8±5.8 kg/m2. Participants in the intervention group lost more weight before pregnancy than those in the control group (-0.25±0.51 vs -0.03±0.21 kg/wk; P<.001). However, participants in the intervention group gained more weight than those in the control group in the second trimester (0.42±0.26 vs 0.33±0.28 kg/wk; P=.04) and third trimester (0.56±0.37 vs 0.43±0.33 kg/wk; P=.02) and overall (13.2±8.20 vs 10.3±7.41 kg; P=.03). Nevertheless, arms did not differ in rates of exceeding gestational weight gain guidelines at any time point. Spontaneous pregnancy loss was less common in the intervention arm than in the control arm (8 [4.9%] vs 19 [11.8%]; odds ratio, 0.39 [0.16-0.92]), but we found no other differences in the secondary or exploratory outcomes. CONCLUSION: Participation in the prepregnancy weight loss intervention had no effect on women's likelihood of exceeding gestational weight gain guidelines. Although the intervention group successfully lost weight before conception, the intervention group was associated with greater weight gain in late pregnancy. To effectively reduce weight throughout pregnancy and improve maternal and child outcomes, prepregnancy weight loss interventions may need to be combined with intensive weight management that continues throughout delivery.

Screening for Vitamin D Deficiency in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Low serum vitamin D levels have been associated with adverse clinical outcomes; identifying and treating deficiency may improve outcomes. Objective: To review the evidence about screening for vitamin D deficiency in adults. Data Sources: PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November 30, 2020. Study Selection: Fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults; nonrandomized controlled intervention studies for harms only. Treatment was limited to studies enrolling or analyzing participants with low serum vitamin D levels. Data Extraction and Synthesis: Two reviewers assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted. Main Outcomes and Measures: Mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection. Results: Forty-six studies (N = 16 205) (77 publications) were included. No studies directly evaluated the health benefits or harms of screening. Among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, -0.6% to 1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, -0.3% [95% CI, -2.1% to 1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, -1.3% to 1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74 to 1.35] and 1.09 [95% CI, 0.68 to 1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68 to 1.39] and 1.01 [95% CI, 0.65 to 1.58], or depression (3 RCTs, various measures reported). The pooled ARD for incidence of participants with 1 or more falls was -4.3% (95% CI, -11.6% to 2.9%; 6 RCTs). The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT). The incidence of adverse events and kidney stones was similar between treatment and control groups. Conclusions and Relevance: No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

Counseling and Behavioral Interventions for Healthy Weight and Weight Gain in Pregnancy: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Counseling and active behavioral interventions to limit excess gestational weight gain (GWG) during pregnancy may improve health outcomes for women and infants. The 2009 National Academy of Medicine (NAM; formerly the Institute of Medicine) recommendations for healthy GWG vary according to prepregnancy weight category. Objective: To review and synthesize the evidence on benefits and harms of behavioral interventions to promote healthy weight gain during pregnancy to inform the US Preventive Services Task Force recommendation. Data Sources: Ovid MEDLINE and the Cochrane Library to March 2020, with surveillance through February 2021. Study Selection: Randomized clinical trials and nonrandomized controlled intervention studies focused on diet, exercise, and/or behavioral counseling interventions on GWG. Data Extraction and Synthesis: Independent data abstraction and study quality rating with dual review. Main Outcomes and Measures: Gestational weight-related outcomes; maternal and infant morbidity and mortality; harms. Results: Sixty-eight studies (N = 25 789) were included. Sixty-seven studies evaluated interventions during pregnancy, and 1 evaluated an intervention prior to pregnancy. GWG interventions were associated with reductions in risk of gestational diabetes (43 trials, n = 19 752; relative risk [RR], 0.87 [95% CI, 0.79 to 0.95]; absolute risk difference [ARD], -1.6%) and emergency cesarean delivery (14 trials, n = 7520; RR, 0.85 [95% CI, 0.74 to 0.96]; ARD, -2.4%). There was no significant association between GWG interventions and risk of gestational hypertension, cesarean delivery, or preeclampsia. GWG interventions were associated with decreased risk of macrosomia (25 trials, n = 13 990; RR, 0.77 [95% CI, 0.65 to 0.92]; ARD, -1.9%) and large for gestational age (26 trials, n = 13 000; RR, 0.89 [95% CI, 0.80 to 0.99]; ARD, -1.3%) but were not associated with preterm birth. Intervention participants experienced reduced weight gain across all prepregnancy weight categories (55 trials, n = 20 090; pooled mean difference, -1.02 kg [95% CI, -1.30 to -0.75]) and demonstrated lower likelihood of GWG in excess of NAM recommendations (39 trials, n = 14 271; RR, 0.83 [95% CI, 0.77 to 0.89]; ARD, -7.6%). GWG interventions were associated with reduced postpartum weight retention at 12 months (10 trials, n = 3957; mean difference, -0.63 kg [95% CI, -1.44 to -0.01]). Data on harms were limited. Conclusions and Relevance: Counseling and active behavioral interventions to limit GWG were associated with decreased risk of gestational diabetes, emergency cesarean delivery, macrosomia, and large for gestational age. GWG interventions were also associated with modest reductions in mean GWG and decreased likelihood of exceeding NAM recommendations for GWG.

Pubertal timing and breast density in young women: a prospective cohort study.

BACKGROUND: Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. METHODS: From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. RESULTS: The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%)). CONCLUSIONS: Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Predicting Fracture Risk in Younger Postmenopausal Women: Comparison of the Garvan and FRAX Risk Calculators in the Women's Health Initiative Study.

BACKGROUND: Guidelines recommend fracture risk assessment in postmenopausal women aged 50-64, but the optimal method is unknown. OBJECTIVES: To compare discrimination and calibration of the Fracture Risk Assessment Tool (FRAX) and Garvan fracture risk calculator for predicting fractures in postmenopausal women aged 50-64 at baseline. DESIGN: Prospective observational study. PARTICIPANTS: Sixty-three thousand seven hundred twenty-three postmenopausal women aged 50-64 years participating in the Women's Health Initiative Observational Study and Clinical Trials. MAIN MEASURES: Incident hip fractures and major osteoporotic fractures (MOF) during 10-year follow-up. Calculated FRAX- and Garvan-predicted hip fracture and MOF fracture probabilities. KEY RESULTS: The observed 10-year hip fracture probability was 0.3% for women aged 50-54 years (n = 14,768), 0.6% for women aged 55-59 years (n = 22,442), and 1.1% for women aged 60-64 years (n = 25,513). At sensitivity thresholds ≥ 80%, specificity of both tools for detecting incident hip fracture during 10 years of follow-up was low: Garvan 30.6% (95% confidence interval [CI] 30.3-31.0%) and FRAX 43.1% (95% CI 42.7-43.5%). At maximal area under the receiver operating characteristic curve (AUC(c), 0.58 for Garvan, 0.65 for FRAX), sensitivity was 16.0% (95% CI 12.7-19.4%) for Garvan and 59.2% (95% CI 54.7-63.7%) for FRAX. At AUC(c) values, sensitivity was lower in African American and Hispanic women than among white women and lower in women aged 50-54 than those 60-64 years old. Observed hip fracture probabilities were similar to FRAX-predicted probabilities but greater than Garvan-predicted probabilities. At AUC(c) values (0.56 for both tools), sensitivity for identifying MOF was also low (range 26.7-46.8%). At AUC(c) values (0.55 for both tools), sensitivity for identifying any clinical fracture ranged from 18.1 to 34.0%. CONCLUSIONS: In postmenopausal women aged 50-64 years, the FRAX and Garvan fracture risk calculator discriminate poorly between women who do and do not experience fracture during 10-year follow-up. There is no useful threshold for either tool.

Establishing an electronic health record-supported approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials: The vitamin D and type 2 diabetes (D2d) study experience.

AIMS: To establish recruitment approaches that leverage electronic health records in multicenter prediabetes/diabetes clinical trials and compare recruitment outcomes between electronic health record-supported and conventional recruitment methods. METHODS: Observational analysis of recruitment approaches in the vitamin D and type 2 diabetes (D2d) study, a multicenter trial in participants with prediabetes. Outcomes were adoption of electronic health record-supported recruitment approaches by sites, number of participants screened, recruitment performance (proportion screened who were randomized), and characteristics of participants from electronic health record-supported versus non-electronic health record methods. RESULTS: In total, 2423 participants were randomized: 1920 from electronic health record (mean age of 60 years, 41% women, 68% White) and 503 from non-electronic health record sources (mean age of 56.9 years, 58% women, 61% White). Electronic health record-supported recruitment was adopted by 21 of 22 sites. Electronic health record-supported recruitment was associated with more participants screened versus non-electronic health record methods (4969 vs 2166 participants screened), higher performance (38.6% vs 22.7%), and more randomizations (1918 vs 505). Participants recruited via electronic health record were older, included fewer women and minorities, and reported higher use of dietary supplements. Electronic health record-supported recruitment was incorporated in diverse clinical environments, engaging clinicians either at the individual or the healthcare system level. CONCLUSION: Establishing electronic health record-supported recruitment approaches across a multicenter prediabetes/diabetes trial is feasible and can be adopted by diverse clinical environments.

Intake of dietary carbohydrates in early adulthood and adolescence and breast density among young women.

PURPOSE: Carbohydrate intake increases postprandial insulin secretion and may affect breast density, a strong risk factor for breast cancer, early in life. We examined associations of adolescent and early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars with breast density among 182 young women. METHODS: Diet was assessed using three 24-h recalls at each of five Dietary Intervention Study in Children (DISC) clinic visits when participants were age 10-19 years and at the DISC06 Follow-Up Study clinic visit when participants were age 25-29 years. Associations between energy-adjusted carbohydrates and MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at 25-29 years were quantified using multivariable-adjusted mixed-effects linear models. RESULTS: Adolescent sucrose intakes and premenarcheal total carbohydrates intakes were modestly associated with higher %DBV (mean %DBVQ1 vs Q4, 16.6 vs 23.5% for sucrose; and 17.2 vs 22.3% for premenarcheal total carbohydrates, all Ptrend ≤ 0.02), but not with ADBV. However, adolescent intakes of fiber and fructose were not associated with %DBV and ADBV. Early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars were not associated with %DBV and ADBV. CONCLUSIONS: Insulinemic carbohydrate diet during puberty may be associated with adulthood breast density, but our findings need replication in larger studies. Clinical Trials Registration ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

Stratified Probabilistic Bias Analysis for Body Mass Index-related Exposure Misclassification in Postmenopausal Women.

BACKGROUND: There is widespread concern about the use of body mass index (BMI) to define obesity status in postmenopausal women because it may not accurately represent an individual's true obesity status. The objective of the present study is to examine and adjust for exposure misclassification bias from using an indirect measure of obesity (BMI) compared with a direct measure of obesity (percent body fat). METHODS: We used data from postmenopausal non-Hispanic black and non-Hispanic white women in the Women's Health Initiative (n=126,459). Within the Women's Health Initiative, a sample of 11,018 women were invited to participate in a sub-study involving dual-energy x-ray absorptiometry scans. We examined indices of validity comparing BMI-defined obesity (≥30 kg/m), with obesity defined by percent body fat. We then used probabilistic bias analysis models stratified by age and race to explore the effect of exposure misclassification on the obesity-mortality relationship. RESULTS: Validation analyses highlight that using a BMI cutpoint of 30 kg/m to define obesity in postmenopausal women is associated with poor validity. There were notable differences in sensitivity by age and race. Results from the stratified bias analysis demonstrated that failing to adjust for exposure misclassification bias results in attenuated estimates of the obesity-mortality relationship. For example, in non-Hispanic white women 50-59 years of age, the conventional risk difference was 0.017 (95% confidence interval = 0.01, 0.023) and the bias-adjusted risk difference was 0.035 (95% simulation interval = 0.028, 0.043). CONCLUSIONS: These results demonstrate the importance of using quantitative bias analysis techniques to account for nondifferential exposure misclassification of BMI-defined obesity. See video abstract at, http://links.lww.com/EDE/B385.

Behavioral and Pharmacotherapy Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Overweight and obesity have been associated with adverse health effects. Objective: To systematically review evidence on benefits and harms of behavioral and pharmacotherapy weight loss and weight loss maintenance interventions in adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed Publisher-Supplied Records, PsycINFO, and the Cochrane Central Register of Controlled Trials for studies published through June 6, 2017; ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials through August 2017; and ongoing surveillance in targeted publications through March 23, 2018. Studies from previous reviews were reevaluated for inclusion. Study Selection: Randomized clinical trials (RCTs) focusing on weight loss or weight loss maintenance in adults. Data Extraction and Synthesis: Data were abstracted by one reviewer and confirmed by another. Random-effects meta-analyses were conducted for weight loss outcomes in behavior-based interventions. Main Outcomes and Measures: Health outcomes, weight loss or weight loss maintenance, reduction in obesity-related conditions, and adverse events. Results: A total of 122 RCTs (N = 62 533) and 2 observational studies (N = 209 993) were identified. Compared with controls, participants in behavior-based interventions had greater mean weight loss at 12 to 18 months (-2.39 kg [95% CI, -2.86 to -1.93]; 67 studies [n = 22065]) and less weight regain (-1.59 kg [95% CI, -2.38 to -0.79]; 8 studies [n = 1408]). Studies of medication-based weight loss and maintenance interventions also reported greater weight loss or less weight regain in intervention compared with placebo groups at 12 to 18 months (range, -0.6 to -5.8 kg; no meta-analysis). Participants with prediabetes in weight loss interventions had a lower risk of developing diabetes compared with controls (relative risk, 0.67 [95% CI, 0.51 to 0.89]). There was no evidence of other benefits, but most health outcomes such as mortality, cardiovascular disease, and cancer were infrequently reported. Small improvements in quality of life in some medication trials were noted but were of unclear clinical significance. There was no evidence of harm such as cardiovascular disease from behavior-based interventions; higher rates of adverse events were associated with higher dropout rates in medication groups than in placebo groups. Conclusions and Relevance: Behavior-based weight loss interventions with or without weight loss medications were associated with more weight loss and a lower risk of developing diabetes than control conditions. Weight loss medications, but not behavior-based interventions, were associated with higher rates of harms. Long-term weight and health outcomes data, as well as data on important subgroups, were limited.

Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Osteoporotic fractures result in significant morbidity and mortality. Objective: To update the evidence for benefits and harms of vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults to inform the US Preventive Services Task Force. Data Sources: PubMed, EMBASE, Cochrane Library, and trial registries through March 21, 2017; references; and experts. Surveillance continued through February 28, 2018. Study Selection: English-language randomized clinical trials (RCTs) or observational studies of supplementation with vitamin D, calcium, or both among adult populations; studies of populations that were institutionalized or had known vitamin D deficiency, osteoporosis, or prior fracture were excluded. Data Extraction and Synthesis: Dual, independent review of titles/abstracts and full-text articles and study quality rating using predefined criteria. Random-effects meta-analysis used when at least 3 similar studies were available. Main Outcomes and Measures: Incident fracture, mortality, kidney stones, cardiovascular events, and cancer. Results: Eleven RCTs (N = 51 419) in adults 50 years and older conducted over 2 to 7 years were included. Compared with placebo, supplementation with vitamin D decreased total fracture incidence (1 RCT [n = 2686]; absolute risk difference [ARD], -2.26% [95% CI, -4.53% to 0.00%]) but had no significant association with hip fracture (3 RCTs [n = 5496]; pooled ARD, -0.01% [95% CI, -0.80% to 0.78%]). Supplementation using vitamin D with calcium had no effect on total fracture incidence (1 RCT [n = 36 282]; ARD, -0.35% [95% CI, -1.02% to 0.31%]) or hip fracture incidence (2 RCTs [n = 36 727]; ARD from the larger trial, -0.14% [95% CI, -0.34% to 0.07%]). The evidence for calcium alone was limited, with only 2 studies (n = 339 total) and very imprecise results. Supplementation with vitamin D alone or with calcium had no significant effect on all-cause mortality or incident cardiovascular disease; ARDs ranged from -1.93% to 1.79%, with CIs consistent with no significant differences. Supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones (3 RCTs [n = 39 213]; pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]), but supplementation with calcium alone was not associated with an increased risk (3 RCTs [n = 1259]; pooled ARD, 0.00% [95% CI, -0.87% to 0.87%]). Supplementation with vitamin D and calcium was not associated with an increase in cancer incidence (3 RCTs [n = 39 213]; pooled ARD, -1.48% [95% CI, -3.32% to 0.35%]). Conclusions and Relevance: Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. Vitamin D with calcium was associated with an increase in the incidence of kidney stones.

Reproductive Risk Factors and Coronary Heart Disease in the Women's Health Initiative Observational Study.

BACKGROUND: Reproductive factors provide an early window into a woman's coronary heart disease (CHD) risk; however, their contribution to CHD risk stratification is uncertain. METHODS AND RESULTS: In the Women's Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C statistic, net reclassification index (or net reclassification index with risk categories of <5%, 5 to <10%, and ≥10% 10-year risk of CHD), and integrated discriminatory index were assessed. Among 72 982 women (CHD events, n=4607; median follow-up,12.0 [interquartile range, 8.3-13.7] years; mean [standard deviation] age, 63.2 [7.2] years), an age-adjusted reproductive risk factor model had a C statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages, and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C statistic increased from 0.726 to 0.730; integrated discriminatory index, 0.0013; P<0.0001). Net reclassification for women with events was not improved (net reclassification index events, 0.007; P=0.18); and, for women without events, net reclassification was marginally improved (net reclassification index nonevents, 0.002; P=0.04) CONCLUSIONS: Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination, and do not materially improve net reclassification.

Anthropometric measures and serum estrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study.

BACKGROUND: Several anthropometric measures have been associated with hormone-related cancers. However, it is unknown whether estrogen metabolism plays an important role in these relationships. We examined whether measured current body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported BMI at age 18 years were associated with serum estrogens/estrogen metabolites using baseline, cross-sectional data from 1835 postmenopausal women enrolled in the Women's Health Initiative Observational Study. METHODS: Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Geometric means (GMs) of estrogens/estrogen metabolites (in picomoles per liter) were estimated using inverse probability weighted linear regression, adjusting for potential confounders and stratified on menopausal hormone therapy (MHT) use. RESULTS: Among never or former MHT users, current BMI (≥30 vs. <25 kg/m2) was positively associated with parent estrogens (multivariable adjusted GM 432 vs. 239 pmol/L for estrone, 74 vs. 46 pmol/L for estradiol; p-trend < 0.001 for both) and all of the 2-, 4-, and 16-pathway estrogen metabolites evaluated (all p-trend ≤ 0.02). After additional adjustment for estradiol, unconjugated methylated 2-catechols were inversely associated (e.g., 2-methoxyestrone multivariable GM 9.3 vs. 12.0 pmol/L; p-trend < 0.001). Among current MHT users, current BMI was not associated with parent estrogens but was inversely associated with methylated catechols (e.g., 2-methoxyestrone multivariable GM 216 vs. 280 pmol/L; p-trend = 0.008). Similar patterns of association were found with WHR; however, the associations were not independent of BMI. Height and BMI at age 18 years were not associated with postmenopausal estrogens/estrogen metabolite levels. CONCLUSIONS: Our data suggest that postmenopausal BMI is associated with increased circulating levels of parent estrogens and reduced methylation of catechol estrogen metabolites, the estrogen metabolism patterns that have previously been associated with higher breast cancer risk.

Risk of Diabetes After Hysterectomy With or Without Oophorectomy in Postmenopausal Women.

The aim of this study was to determine the associations between hysterectomy, bilateral salpingo-oophorectomy (BSO), and incidence of diabetes in postmenopausal women participating in the Women's Health Initiative (WHI), a series of trials conducted in the United States, during the period 1993-1998. A total of 67,130 postmenopausal women aged 50-79 years were followed for a mean of 13.4 years. Among them, 7,430 cases of diabetes were diagnosed. Multivariable Cox proportional hazards models were used to assess the association between hysterectomy/oophorectomy status and diabetes incidence. Compared with women without hysterectomy, women with hysterectomy had a significantly higher risk of diabetes (hazard ratio = 1.13, 95% confidence interval: 1.06, 1.21). The increased risk of diabetes was similar for women with hysterectomy only and for women with hysterectomy with concomitant BSO. Compared with hysterectomy alone, hysterectomy with BSO was not associated with additional risk of diabetes after stratification by age at hysterectomy and hormone therapy status. In our large, prospective study, we observed that hysterectomy, regardless of oophorectomy status, was associated with increased risk of diabetes among postmenopausal women. However, our data did not support the hypothesis that early loss of ovarian estrogens is a risk factor for type 2 diabetes. The modest increased risk of diabetes associated with hysterectomy may be due to residual confounding, such as the reasons for hysterectomy.

Lean body mass and risk of incident atrial fibrillation in post-menopausal women.

AIMS: High body mass index (BMI) is a risk factor for atrial fibrillation (AF). The aim of this study was to determine whether lean body mass (LBM) predicts AF. METHODS AND RESULTS: The Women's Health Initiative is a study of post-menopausal women aged 50-79 enrolled at 40 US centres from 1994 to 1998. A subset of 11 393 participants at three centres underwent dual-energy X-ray absorptiometry. Baseline demographics and clinical histories were recorded. Incident AF was identified using hospitalization records and diagnostic codes from Medicare claims. A multivariable Cox hazard regression model adjusted for demographic and clinical risk factors was used to evaluate associations between components of body composition and AF risk. After exclusion for prevalent AF or incomplete data, 8832 participants with an average age of 63.3 years remained for analysis. Over the 11.6 years of average follow-up time, 1035 women developed incident AF. After covariate adjustment, all measures of LBM were independently associated with higher rates of AF: total LBM [hazard ratio (HR) 1.24 per 5 kg increase, 95% confidence intervals (CI) 1.14-1.34], central LBM (HR 1.51 per 5 kg increase, 95% CI 1.31-1.74), and peripheral LBM (HR 1.39 per 5 kg increase, 95% CI 1.19-1.63). The association between total LBM and AF remained significant after adjustment for total fat mass (HR 1.22 per 5 kg increase, 95% CI 1.13-1.31). CONCLUSION: Greater LBM is a strong independent risk factor for AF. After adjusting for obesity-related risk factors, the risk of AF conferred by higher BMI is primarily driven by the association between LBM and AF.