Type I error control for cluster randomized trials under varying small sample structures.

BACKGROUND: Linear mixed models (LMM) are a common approach to analyzing data from cluster randomized trials (CRTs). Inference on parameters can be performed via Wald tests or likelihood ratio tests (LRT), but both approaches may give incorrect Type I error rates in common finite sample settings. The impact of different combinations of cluster size, number of clusters, intraclass correlation coefficient (ICC), and analysis approach on Type I error rates has not been well studied. Reviews of published CRTs find that small sample sizes are not uncommon, so the performance of different inferential approaches in these settings can guide data analysts to the best choices. METHODS: Using a random-intercept LMM stucture, we use simulations to study Type I error rates with the LRT and Wald test with different degrees of freedom (DF) choices across different combinations of cluster size, number of clusters, and ICC. RESULTS: Our simulations show that the LRT can be anti-conservative when the ICC is large and the number of clusters is small, with the effect most pronouced when the cluster size is relatively large. Wald tests with the between-within DF method or the Satterthwaite DF approximation maintain Type I error control at the stated level, though they are conservative when the number of clusters, the cluster size, and the ICC are small. CONCLUSIONS: Depending on the structure of the CRT, analysts should choose a hypothesis testing approach that will maintain the appropriate Type I error rate for their data. Wald tests with the Satterthwaite DF approximation work well in many circumstances, but in other cases the LRT may have Type I error rates closer to the nominal level.

The Linked CENTURY Study: linking three decades of clinical and public health data to examine disparities in childhood obesity.

BACKGROUND: Despite the need to identify the causes of disparities in childhood obesity, the existing epidemiologic studies of early life risk factors have several limitations. We report on the construction of the Linked CENTURY database, incorporating CENTURY (Collecting Electronic Nutrition Trajectory Data Using Records of Youth) Study data with birth certificates; and discuss the potential implications of combining clinical and public health data sources in examining the etiology of disparities in childhood obesity. METHODS: We linked the existing CENTURY Study, a database of 269,959 singleton children from birth to age 18 years with measured heights and weights, with each child's Massachusetts birth certificate, which captures information on their mothers' pregnancy history and detailed socio-demographic information of both mothers and fathers. RESULTS: Overall, 74.2 % were matched, resulting in 200,343 children in the Linked CENTURY Study with 1,580,597 well child visits. Among this cohort, 94.0 % (188,334) of children have some father information available on the birth certificate and 60.9 % (121,917) of children have at least one other sibling in the dataset. Using maternal race/ethnicity from the birth certificate as an indicator of children's race/ethnicity, 75.7 % of children were white, 11.6 % black, 4.6 % Hispanic, and 5.7 % Asian. Based on socio-demographic information from the birth certificate, 20.0 % of mothers were non-US born, 5.9 % smoked during pregnancy, 76.3 % initiated breastfeeding, and 11.0 % of mothers had their delivery paid for by public health insurance. Using clinical data from the CENTURY Study, 22.7 % of children had a weight-for-length ≥ 95(th) percentile between 1 and 24 months and 12.0 % of children had a body mass index ≥ 95(th) percentile at ages 5 and 17 years. CONCLUSIONS: By linking routinely-collected data sources, it is possible to address research questions that could not be answered with either source alone. Linkage between a clinical database and each child's birth certificate has created a unique dataset with nearly complete racial/ethnic and socio-demographic information from both parents, which has the potential to examine the etiology of racial/ethnic and socioeconomic disparities in childhood obesity.

Associations of trimester-specific gestational weight gain with maternal adiposity and systolic blood pressure at 3 and 7 years postpartum.

OBJECTIVE: Our objective was to examine the associations of total and trimester-specific gestational weight gain (GWG) rate with postpartum maternal weight and cardiometabolic risk. We hypothesized that first-trimester GWG would be most strongly associated with long-term maternal health. STUDY DESIGN: We studied 801 women enrolled during the first trimester of pregnancy in the Boston-area Project Viva cohort 1999 through 2002. At 3 years postpartum we measured maternal weight, waist circumference (WC), and systolic blood pressure (SBP) and collected fasting blood from a subset. At 7 years postpartum we again measured weight and WC. We used multivariable linear regression to evaluate relations of total and trimester-specific GWG rate with weight change (vs self-reported prepregnancy weight) and WC at each time point, stratified by prepregnancy weight, as well as associations with SBP and insulin resistance at 3 years. RESULTS: Median age at enrollment was 34.0 years (range, 16.4-44.9); 65% were white. Mean (SD) total GWG rate was 0.38 (0.14) kg/wk. Women gained weight faster during the second (0.47 [0.19] kg/wk) and third (0.44 [0.22] kg/wk) trimesters than the first (0.22 [0.22] kg/wk). Total and first-trimester GWG rate were most strongly associated with postpartum weight change. Among normal-weight women, each 1-SD increase in total and first-trimester GWG rate corresponded with 0.85 (95% confidence interval [CI], 0.07-1.63) kg and 2.08 (1.32-2.84) kg greater weight change at 3 and 7 years postpartum, respectively, but there was not strong evidence of association for either second- (-0.30 kg; 95% CI, -1.08 to 0.48) or third- (-0.26 kg; 95% CI, -1.08 to 0.55) trimester GWG. First-trimester GWG rate also related to 3-year postpartum weight change in overweight (2.28 kg; 95% CI, 0.95-3.61) and obese (2.47 kg; 95% CI, 0.98-3.97) women. Greater total and first-trimester GWG rate were associated with larger WC and higher SBP but not insulin resistance. CONCLUSION: In this observational cohort, first-trimester weight gain was more strongly associated with maternal weight retention as well as higher WC and blood pressure than second- or third-trimester gain. Interventions targeting GWG beginning very early in pregnancy may benefit long-term maternal health.

Racial/ethnic and immigrant differences in early childhood diet quality.

OBJECTIVE: To assess racial/ethnic differences in the diet in young children and the explanatory role of maternal BMI, immigrant status and perception of child's weight. DESIGN: Among white, black and Hispanic 3-year-olds, we used negative binomial and linear regression to examine associations of race/ethnicity with foods and nutrients assessed by a validated FFQ. SETTING: Project Viva, Boston (MA), USA. SUBJECTS: Children aged 3 years (n 898). RESULTS: Mean age was 38·3 (sd 2·8) months; 464 (52 %) were boys and 127 mothers (14 %) were immigrants. After adjustment for sociodemographic factors, black and Hispanic children (v. white) had a higher intake of sugar-sweetened beverages (rate ratio (RR) = 2·59 (95 % CI 1·95, 3·48) and RR = 1·59 (95 % CI 1·07, 2·47), respectively) and lower intakes of skimmed/1 % milk (RR = 0·42 (95 % CI 0·33, 0·53) and RR = 0·43 (95 % CI 0·31, 0·61), respectively) and trans-fat (-0·10 (95 % CI -0·18, -0·03) % of energy and -0·15 (95 % CI -0·26, -0·04) % of energy, respectively). Among Hispanics only, a lower intake of snack food (RR = 0·83 (95 % CI 0·72, 0·98)) was found and among blacks only, a higher intake of fast food (RR = 1·28 (95 % CI 1·05, 1·55)) and lower intakes of saturated fat (-0·86 (95 % CI -1·48, -0·23) % of energy), dietary fibre (0·85 (95 % CI 0·08, 1·62) g/d) and Ca (-120 (95 % CI -175, -65) mg/d) were found. Being born outside the USA was associated with more healthful nutrient intakes and less fast food. CONCLUSIONS: Three-year-old black and Hispanic (v. white) children ate more sugar-sweetened beverages and less low-fat dairy. Total energy intake was substantially higher in Hispanic children. Snack food (Hispanic children) and fat intakes (black children) tended to be lower. Children of immigrants ate less fast food and bad fats and more fibre.

Correlations among adiposity measures in school-aged children.

BACKGROUND: Given that it is not feasible to use dual x-ray absorptiometry (DXA) or other reference methods to measure adiposity in all pediatric clinical and research settings, it is important to identify reasonable alternatives. Therefore, we sought to determine the extent to which other adiposity measures were correlated with DXA fat mass in school-aged children. METHODS: In 1110 children aged 6.5-10.9 years in the pre-birth cohort Project Viva, we calculated Spearman correlation coefficients between DXA (n=875) and other adiposity measures including body mass index (BMI), skinfold thickness, circumferences, and bioimpedance. We also computed correlations between lean body mass measures. RESULTS: 50.0% of the children were female and 36.5% were non-white. Mean (SD) BMI was 17.2 (3.1) and total fat mass by DXA was 7.5 (3.9) kg. DXA total fat mass was highly correlated with BMI (r(s)=0.83), bioimpedance total fat (r(s)=0.87), and sum of skinfolds (r(s)=0.90), and DXA trunk fat was highly correlated with waist circumference (r(s)=0.79). Correlations of BMI with other adiposity indices were high, e.g., with waist circumference (r(s)=0.86) and sum of subscapular plus triceps skinfolds (r(s)=0.79). DXA fat-free mass and bioimpedance fat-free mass were highly correlated (r(s)=0.94). CONCLUSIONS: In school-aged children, BMI, sum of skinfolds, and other adiposity measures were strongly correlated with DXA fat mass. Although these measurement methods have limitations, BMI and skinfolds are adequate surrogate measures of relative adiposity in children when DXA is not practical.

Using a Microsimulation of Energy Balance to Explore the Influence of Prenatal Sugar-Sweetened Beverage Intake on Child BMI.

OBJECTIVE: Experiments with animals suggest that high sugar consumption during pregnancy may predispose offspring to obesity, but few human studies have examined this relationship. This study explored the association between the consumption of sugar-sweetened beverages (SSBs) during pregnancy and caloric intake through childhood. METHODS: Using cohort data on child weight, height, and physical activity levels, a lab-validated microsimulation model of energy balance was employed to infer the caloric intake of children through age 11 years. Random effects models were then employed to explore the relationships between prenatal maternal consumption and inferred caloric intake during childhood. RESULTS: An additional daily serving of SSBs during the second trimester of pregnancy was associated with an increase in child consumption of 13 kcal/d (95% CI: 1.2-26.8). Age-stratified models adjusting for maternal and child covariates suggested that this association was strongest for children aged 2.5 to 5.5 years. The consumption of SSBs during the first trimester was not found to have a consistently positive relationship to caloric intake. CONCLUSIONS: These findings suggest that SSB consumption during the second trimester of pregnancy is associated with child energy intake and may influence anthropometry in early childhood, which is consistent with and suggestive of the presence of biological causal pathways alongside likely simultaneous contributions of social and environmental influences.

Per- and polyfluoroalkyl substances and kidney function: Follow-up results from the Diabetes Prevention Program trial.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in populations worldwide and may hinder kidney function. The objective of the study was to determine longitudinal associations of plasma PFAS concentrations with estimated glomerular filtration rate (eGFR) and evaluate whether a lifestyle intervention modify the associations. We studied 875 participants initially randomized to the lifestyle or placebo arms in the Diabetes Prevention Program (DPP, 1996-2002) trial and Outcomes Study (DPPOS, 2002-2014). We ran generalized linear mixed models accounting a priori covariates to evaluate the associations between baseline PFAS concentrations and repeated measures of eGFR, separately, for six PFAS (PFOS, PFOA, PFHxS, EtFOSAA, MeFOSAA, PFNA); then used quantile-based g-computation to evaluate the effects of the six PFAS chemicals as a mixture. The cohort was 64.9% female; 73.4% 40-64 years-old; 29.4% with hypertension; 50.5% randomized to lifestyle intervention and 49.5% to placebo and had similar plasma PFAS concentrations as the general U.S. population in 1999-2000. Most participants had normal kidney function (eGFR > 90 mL/min/1.73 m2) over the approximately 14 years of follow-up. We found that plasma PFAS concentrations during DPP were inversely associated with eGFR during DPPOS follow-up. Each quartile increase in baseline plasma concentration of the 6 PFAS as a mixture was associated with 2.26 mL/min/1.73 m2 lower eGFR (95% CI: -4.12, -0.39) at DPPOS Year 5, approximately 9 years since DPP randomization and PFAS measurements. The lifestyle intervention did not modify associations, but inverse associations were stronger among participants with hypertension at baseline. Among prediabetic adults, we found inverse associations between baseline plasma PFAS concentrations and measures of eGFR throughout 14 years of follow-up. The lifestyle intervention of diet, exercise and behavioral changes did not modify the associations, but persons with hypertension may have heightened susceptibility.

Temporal trends of concentrations of per- and polyfluoroalkyl substances among adults with overweight and obesity in the United States: Results from the Diabetes Prevention Program and NHANES.

BACKGROUND: Understanding the temporal trends and change of concentrations of per- and polyfluoroalkyl substances (PFAS) is important to evaluate the health impact of PFAS at both the individual- and population-level, however, limited information is available for pre-diabetic adults in the U.S. OBJECTIVES: Determine trends and rate of change of plasma PFAS concentrations in overweight or obese U.S. adults and evaluate variation by sex, race/ethnicity, and age. METHODS: We described temporal trends of plasma PFAS concentrations using samples collected in 1996-1998, 1999-2001, and 2011-2012 from 957 pre-diabetic adults enrolled in the Diabetes Prevention Program (DPP) trial and Outcomes Study (DPPOS) and compared to serum concentrations from the National Health and Nutrition Examination Survey (NHANES 1999-2000, 2003-2016, adults with BMI ≥ 24 kg/m2). We examined associations between participants' characteristics and PFAS concentrations and estimated the rate of change using repeated measures in DPP/DPPOS assuming a first-order elimination model. RESULTS: Longitudinal measures of PFAS concentrations in DPP/DPPOS individuals were comparable to NHANES cross-sectional populational means. Plasma concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid, perfluorohexanesulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), and N-methylperfluorooctane sulfonamido acetic acid (MeFOSAA) started to decline after the year 2000 and concentrations of perfluorononanoic acid (PFNA) increased after 2000 and, for NHANES, decreased after 2012. We consistently observed higher PFOS, PFHxS and PFNA among male, compared to female, and higher PFOS and PFNA among Black, compared to white, participants. The estimated time for concentrations to decrease by half ranged from 3.39 years for EtFOSAA to 17.56 years for PFHxS. DISCUSSION: We observed a downward temporal trend in plasma PFOS concentrations that was consistent with the timing for U.S. manufacturers' phaseout. Male and Black participants consistently showed higher PFOS and PFNA than female and white participants, likely due to differences in exposure patterns, metabolism or elimination kinetics.

Per- and polyfluoroalkyl substances and calcifications of the coronary and aortic arteries in adults with prediabetes: Results from the diabetes prevention program outcomes study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification. METHODS AND RESULTS: This study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC > 11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR = 1.26 (95% CI:1.08, 1.47) for moderate CAC and OR = 1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR = 1.67 (95% CI:1.10, 2.54) and OR = 1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes. CONCLUSIONS: Prediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.

Use of outcomes to evaluate surveillance systems for bioterrorist attacks.

BACKGROUND: Syndromic surveillance systems can potentially be used to detect a bioterrorist attack earlier than traditional surveillance, by virtue of their near real-time analysis of relevant data. Receiver operator characteristic (ROC) curve analysis using the area under the curve (AUC) as a comparison metric has been recommended as a practical evaluation tool for syndromic surveillance systems, yet traditional ROC curves do not account for timeliness of detection or subsequent time-dependent health outcomes. METHODS: Using a decision-analytic approach, we predicted outcomes, measured in lives, quality adjusted life years (QALYs), and costs, for a series of simulated bioterrorist attacks. We then evaluated seven detection algorithms applied to syndromic surveillance data using outcomes-weighted ROC curves compared to simple ROC curves and timeliness-weighted ROC curves. We performed sensitivity analyses by varying the model inputs between best and worst case scenarios and by applying different methods of AUC calculation. RESULTS: The decision analytic model results indicate that if a surveillance system was successful in detecting an attack, and measures were immediately taken to deliver treatment to the population, the lives, QALYs and dollars lost could be reduced considerably. The ROC curve analysis shows that the incorporation of outcomes into the evaluation metric has an important effect on the apparent performance of the surveillance systems. The relative order of performance is also heavily dependent on the choice of AUC calculation method. CONCLUSIONS: This study demonstrates the importance of accounting for mortality, morbidity and costs in the evaluation of syndromic surveillance systems. Incorporating these outcomes into the ROC curve analysis allows for more accurate identification of the optimal method for signaling a possible bioterrorist attack. In addition, the parameters used to construct an ROC curve should be given careful consideration.

Per- and polyfluoroalkyl substances and blood pressure in pre-diabetic adults-cross-sectional and longitudinal analyses of the diabetes prevention program outcomes study.

The relationship of plasma concentration of per- and polyfluoroalkyl substances (PFAS) with blood pressure (BP) is uncertain. This study examined cross-sectional and prospective associations of PFAS with BP and hypertension. We quantified plasma PFAS concentrations from 957 participants enrolled in the lifestyle and placebo arms of the Diabetes Prevention Program (DPP), a randomized controlled trial with approximately 15 years of follow-up. We used multivariable linear and logistic regressions to test cross-sectional associations of six PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), N-methyl-perfluorooctane sulfonamido acetic acid (MeFOSAA), and perfluorononanoic acid (PFNA), with BP and hypertension prevalence, respectively, at baseline. We used generalized linear mixed models to estimate longitudinal associations between baseline PFAS and the rate of BP changes, and Cox-Proportional hazard models to estimate risk of developing hypertension relative to baseline PFAS. Models were adjusted for baseline age, sex, race/ethnicity, treatment arm, educational attainment, income, marital status, smoking habit, alcohol drinking, and diet. We tested for effect modification by the treatment arm and sex, and accounted for multiple comparisons using the False-Discovery Rate (FDR). PFAS concentrations and hypertension prevalence within the study population (65.3% female, 57.7% White, 65.3% aged 40-59 years) were comparable to the general U.S. population. Cross-sectionally, we found small but statistically significant associations of baseline plasma concentrations of PFOA with systolic BP (ß per doubling: 1.49 mmHg, 95% CI: 0.29, 2.70); and MeFOSAA with hypertension (RR = 1.09 per doubling, 95% CI: 1.01, 1.19). Estimates were not statistically significant after FDR adjustment. Longitudinally, we observed null associations in the placebo arm, but some inverse associations of baseline PFOS and MeFOSAA with systolic BP in the lifestyle arm, perhaps due to regression toward the mean. Baseline PFAS concentrations also were not prospectively associated with hypertension risk. Overall, there were modest and mostly null associations of plasma PFAS concentrations with BP and hypertension.

Dietary characteristics associated with plasma concentrations of per- and polyfluoroalkyl substances among adults with pre-diabetes: Cross-sectional results from the Diabetes Prevention Program Trial.

Diet is assumed to be the main source of exposure to per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations, but studies on the diet-PFAS relationship in the United States are scarce. We extracted multiple dietary variables, including daily intakes of food group, diet scores, and dietary patterns, from self-reported dietary data collected at baseline (1996-1999) from adults with pre-diabetes enrolled in the Diabetes Prevention Program, and used linear regression models to evaluate relationships of each dietary variable with plasma concentrations of six PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), perfluorononanoic acid (PFNA) adjusting for covariates. Participants (N = 941, 65% female, 58% Caucasian, 68% married, 75% with higher education, 95% nonsmoker) had similar PFAS concentrations compared to the general U.S. population during 1999-2000. Using a single food group approach, fried fish, other fish/shellfish, meat and poultry had positive associations with most PFAS plasma concentrations. The strongest effect estimate detected was between fried fish and PFNA [13.6% (95% CI: 7.7, 19.9) increase in median concentration per SD increase]. Low-carbohydrate and high protein diet score had positive association with plasma PFHxS. Some food groups, mostly vegetables and fruits, and the Dietary Approaches to Stop Hypertension diet score had inverse associations with PFOS and MeFOSAA. A vegetable diet pattern was associated with lower plasma concentrations of MeFOSAA, while high-fat meat and low-fiber and high-fat grains diet patterns were associated with higher plasma concentrations of PFOS, PFHxS, MeFOSAA and PFNA. We summarized four major dietary characteristics associated with variations in PFAS plasma concentrations in this population. Specifically, consuming more meat/fish/shellfish (especially fried fish, and excluding Omega3-rich fish), low-fiber and high-fat bread/cereal/rice/pasta, and coffee/tea was associated with higher plasma concentrations while dietary patterns of vegetables, fruits and Omega-3 rich fish were associated with lower plasma concentrations of some PFAS.

Actin depolymerizing factor is essential for viability in plants, and its phosphoregulation is important for tip growth.

Actin depolymerizing factor (ADF)/cofilin is important for regulating actin dynamics, and in plants is thought to be required for tip growth. However, the degree to which ADF is necessary has been elusive because of the presence of multiple ADF isoforms in many plant species. In the moss Physcomitrella patens, ADF is encoded by a single, intronless gene. We used RNA interference to demonstrate that ADF is essential for plant viability. Loss of ADF dramatically alters the organization of the F-actin cytoskeleton, and leads to an inhibition of tip growth. We show that ADF is subject to phosphorylation in vivo, and using complementation studies we show that mutations of the predicted phosphorylation site partially rescue plant viability, but with differential affects on tip growth. Specifically, the unphosphorylatable ADF S6A mutant generates small polarized plants with normal F-actin organization, whereas the phosphomimetic S6D mutant generates small, unpolarized plants with a disorganized F-actin cytoskeleton. These data indicate that phosphoregulation at serine 6 is required for full ADF function in vivo, and, in particular, that the interaction between ADF and actin is important for tip growth.

Associations of gestational weight gain with short- and longer-term maternal and child health outcomes.

The authors investigated the rate of gestational weight gain associated with the lowest combined risk of 5 short- and longer-term maternal and child health outcomes for 2,012 mother-child pairs recruited in 1999-2002 into Project Viva, a prebirth cohort study in Massachusetts. Within each maternal prepregnancy body mass index (BMI, kg/m(2)) stratum, they performed a logistic regression analysis predicting all 5 outcomes, from which they determined the rate of gain at which average predicted prevalence of the adverse outcomes was the lowest. The mean rate of total gestational weight gain was 0.39 kg/week (standard deviation, 0.14). The prevalence of small for gestational age was 6%, large for gestational age was 14%, preterm delivery was 7%, substantial postpartum weight retention was 16%, and child obesity was 10%. The lowest predicted outcome prevalence occurred with a 0.28-kg/week gain for women whose BMI was 18.5-24.9, a 0.03-kg/week loss for a BMI of 25.0-29.9, and a 0.19-kg/week loss for a BMI of >or=30.0 kg/m(2)--the lowest observed weight changes in overweight and obese women. For normal-weight and overweight women, lowest-risk gains varied modestly with adjustment for maternal characteristics and with different outcome weightings. For obese women, the lowest-risk weight change was weight loss in all models. Recommendations for gestational weight gain for obese women should be revised.

Weight gain in pregnancy and risk of maternal hyperglycemia.

OBJECTIVE: The purpose of this study was to examine associations of weight gain from prepregnancy to glycemic screening with glucose tolerance status. STUDY DESIGN: Main outcomes were failed glycemic screening (1-hour glucose result >or= 140 mg/dL) with either 1 high value on 3-hour oral glucose tolerance testing (impaired glucose tolerance in pregnancy) or >or= 2 high values on 3-hour oral glucose tolerance testing (gestational diabetes mellitus). We performed multinomial logistic regression to determine the odds of these glucose intolerance outcomes by quartile of gestational weight gain among 1960 women in Project Viva. RESULTS: Mean gestational weight gain was 10.2 +/- 4.3 (SD) kg. Compared with the lowest quartile of weight gain, participants in the highest quartile had an increased odds of impaired glucose tolerance in pregnancy (adjusted odds ratio, 2.54; 95% confidence interval, 1.25-5.15), but not gestational diabetes mellitus (odds ratio, 0.93; 95% confidence interval, 0.50-1.70). CONCLUSION: Higher weight gain predicted impaired glucose tolerance in pregnancy, but not gestational diabetes mellitus.

Cancer screening before and after switching to a high-deductible health plan.

BACKGROUND: Health plans with high deductibles could lead patients to avoid preventive care, such as cancer screening. OBJECTIVE: To determine the effect of membership in a high-deductible health plan on cervical, breast, and colorectal cancer screening. DESIGN: Before-after comparison between groups. SETTING: A high-deductible health plan and an HMO in Massachusetts. The high-deductible health plan fully covered mammography, Papanicolaou tests, and fecal occult blood testing (FOBT) but not colonoscopy, flexible sigmoidoscopy, or double-contrast barium enema (DCBE). PARTICIPANTS: 3169 high-deductible health plan members and 27,022 HMO members (who served as controls). MEASUREMENTS: Change in the proportions of patients undergoing breast, cervical, and colorectal cancer screening. RESULTS: Cancer screening in the high-deductible health plan group was unchanged from baseline to follow-up (adjusted ratios of change, 1.04 [95% CI, 0.91 to 1.19] for breast cancer, 1.04 [CI, 0.92 to 1.17] for cervical cancer, and 1.02 [CI, 0.89 to 1.16] for colorectal cancer). High-deductible health plan members had colonoscopy, flexible sigmoidoscopy, and DCBE less often (ratio of change, 0.73 [CI, 0.56 to 0.95]) and FOBT more often (ratio of change, 1.16 [CI, 1.01 to 1.33]) than HMO members. LIMITATIONS: Population screening frequency was probably underestimated because the study could not assess screening before the baseline year. The study may have included people ineligible for screening because of previous colectomy, mastectomy, or hysterectomy. The findings are limited to a population with relatively high socioeconomic status, which is typical of employed, commercially insured populations. CONCLUSION: Members of a high-deductible health plan did not seem to change their use of breast, cervical, and colorectal cancer screening when tests were fully covered. However, members may have substituted a fully covered screening test (FOBT) for tests subject to the deductible (colonoscopy, flexible sigmoidoscopy, and DCBE).

A 2017 US Reference for Singleton Birth Weight Percentiles Using Obstetric Estimates of Gestation.

OBJECTIVE: To provide an updated birth weight-for-gestational age (BW-for-GA) reference in the United States by using the most recent, nationally representative birth data with obstetric estimates of gestational age (GA). METHODS: We abstracted 3 285 552 singleton births between 22 and 42 weeks' gestation with nonmissing race and/or ethnicity, infant sex, parity, birth weight, and obstetric estimate of GA from the 2017 US natality files. We used 2 techniques (nonlinear, resistant smoothing [4253H] and lambda-mu-sigma) to derive smoothed BW-for-GA curves and compared resulting BW-for-GA cut-points at the third, 10th, 90th, and 97th percentiles with US references from 1999 to 2009. RESULTS: The smoothed BW-for-GA curves from both techniques overlapped considerably with each other, with strong agreements seen between the 2 techniques (>99% agreement; κ-statistic >0.9) for BW-for-GA cut-points at the third, 10th, 90th, and 97th percentiles across all GAs. Cut-points from 2017 using the lambda-mu-sigma method captured 9.8% to 10.2% of births <10th and >90th percentiles and 2.6% to 3.3% of births below the third and above the 97th percentile across all GAs. However, cut-points from US references in 1999 and 2009 (when GA was based on last menstrual period) captured a much larger range of proportions of 2017 births at these thresholds, especially among preterm and postterm GA categories. CONCLUSIONS: We have provided an updated BW-for-GA reference in the United States using the most recent births with obstetric estimates of GA and information to calculate continuous measures of birth size that are sex or parity specific.

Patterns of body mass index milestones in early life and cardiometabolic risk in early adolescence.

BACKGROUND: Few studies have examined the independent and combined relationships of body mass index (BMI) peak and rebound with adiposity, insulin resistance and metabolic risk later in life. We used data from Project Viva, a well-characterized birth cohort from Boston with repeated measures of BMI, to help fill this gap. METHODS: Among 1681 children with BMI data from birth to mid childhood, we fitted individual BMI trajectories using mixed-effects models with natural cubic splines and estimated age, and magnitude of BMI, at peak (in infancy) and rebound (in early childhood). We obtained cardiometabolic measures of the children in early adolescence (median 12.9 years) and analysed their associations with the BMI parameters. RESULTS: After adjusting for potential confounders, age and magnitude at infancy BMI peak were associated with greater adolescent adiposity, and earlier adiposity rebound was strongly associated with greater adiposity, insulin resistance and metabolic risk score independently of BMI peak. Children with a normal timing of BMI peak plus early rebound had an adverse cardiometabolic profile, characterized by higher fat mass index {ß 2.2 kg/m2 [95% confidence interval (CI) 1.6, 2.9]}, trunk fat mass index [1.1 kg/m2 (0.8, 1.5)], insulin resistance [0.2 units (0.04, 0.4)] and metabolic risk score [0.4 units (0.2, 0.5)] compared with children with a normal BMI peak and a normal rebound pattern. Children without a BMI peak (no decline in BMI after the rise in infancy) also had adverse adolescent metabolic profiles. CONCLUSIONS: Early age at BMI rebound is a strong risk factor for cardiometabolic risk, independent of BMI peak. Children with a normal peak-early rebound pattern, or without any BMI decline following infancy, are at greatest risk of adverse cardiometabolic profile in adolescence. Routine monitoring of BMI may help to identify children who are at greatest risk of developing an adverse cardiometabolic profile in later life and who may be targeted for preventive interventions.

Per- and polyfluoroalkyl substances and blood lipid levels in pre-diabetic adults-longitudinal analysis of the diabetes prevention program outcomes study.

Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with lipid regulation. However, most previous studies were cross-sectional with the risk of reverse causation, suggesting a need for long-term prospective studies. We examined the relationship of baseline plasma PFAS concentrations with repeated measures of blood lipids. We included 888 prediabetic adults from the Diabetes Prevention Program (DPP) and DPP Outcomes Study, who had measurements of 6 plasma PFAS concentrations at baseline (1996-1999) and repeated measures of blood lipids over 15 years of follow-up, and were initially randomized to placebo or a lifestyle intervention. We used linear regression to examine cross-sectional associations of PFAS concentrations and lipid levels at baseline, and evaluated prospective risks of hypercholesterolemia and hypertriglyceridemia using Cox proportional hazard models, and tested for effect modification by study arm. Participants (65.9% female, 57.0% White, 65.9% aged 40-59 years) had comparable PFAS concentrations [e.g., median (IQR) perfluorooctanoic acid (PFOA) 4.9 ng/mL (3.2)] with the general U.S. population in 1999-2000. We observed higher total cholesterol at baseline per doubling of PFOA (ß: 6.1 mg/dL, 95% CI: 3.1, 9.04), perfluorohexane sulfonic acid (PFHxS, ß: 2.2 mg/dL, 95% CI: 0.2, 4.3), and perfluorononanoic acid (PFNA, ß: 2.9 mg/dL, 95% CI: 0.7, 5.0). Prospectively, baseline concentrations of several PFASs, including PFOA, PFOS, PFHxS and PFNA, predicted higher risks of incident hypercholesterolemia and hypertriglyceridemia, but only in the placebo group and not the lifestyle intervention group. For example, participants in the placebo group with PFOA concentration > median (4.9 ng/mL) were almost twice as likely (HR: 1.90, 95% CI: 1.25, 2.88) to develop hypertriglyceridemia compared to those ≤median. Findings suggest adverse effects of some PFASs on lipid profiles in prediabetic adults. However, the detrimental effect was attenuated with a lifestyle intervention.

Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Incident Diabetes and Microvascular Disease.

OBJECTIVE: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are suspected endocrine disruptors widely detected across populations. We examine the extent to which PFASs are associated with diabetes incidence and microvascular disease. Secondarily, we tested whether a lifestyle intervention modifies associations and decreases concentrations. RESEARCH DESIGN AND METHODS: We analyzed data from a prospective cohort of 957 participants from the Diabetes Prevention Program (DPP) trial and Diabetes Prevention Program Outcomes Study (DPPOS). At baseline, participants were randomized to an intensive lifestyle intervention of diet, physical activity, and behavior modification or a placebo medication. We quantified plasma concentrations of six PFASs at baseline and 2 years after randomization. Participants were monitored for ∼15 years, repeatedly tested for diabetes, and evaluated for microvascular disease at the end of the follow-up. RESULTS: A doubling in baseline branched perfluorooctanoic acid concentration was associated with a 14% increase in diabetes risk for the placebo (hazard ratio [HR] 1.14, 95% CI 1.04, 1.25) but not in the lifestyle intervention group (HR 1.01, 95% CI 0.92, 1.11, P interaction = 0.11). Mean change in plasma baseline branched perfluorooctanoic acid concentration was greater for the placebo (0.96 ng/mL; 95% CI 0.71, 1.22) compared with the lifestyle intervention group (0.31 ng/mL; 95% CI 0.14, 0.48) 2 years after randomization. Each doubling in N-ethyl-perfluorooctane sulfonamido acetic acid was associated with 17% greater odds of prevalent microvascular disease (OR 1.17, 95% CI 1.05, 1.31), and a similar association was observed for perfluorodimethylhexane sulfonic acid (OR 1.18, 95% CI 1.04, 1.35), regardless of treatment. CONCLUSIONS: Some plasma PFASs were associated with diabetes and microvascular disease. Our results suggest that exercise and diet may attenuate the diabetogenic association of PFASs.