Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death.

BACKGROUND: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. METHODS: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio either to receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. RESULTS: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). CONCLUSIONS: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

Partial Identification of the Effects of Sustained Treatment Strategies.

Although many epidemiologic studies focus on point identification, it is also possible to partially identify causal effects under consistency and the data alone. However, the literature on the so-called "assumption-free" bounds has focused on settings with time-fixed exposures. We describe assumption-free bounds for the effects of both static and dynamic sustained interventions. To provide intuition for the width of the bounds, we also discuss a mathematical connection between assumption-free bounds and clone-censor-weight approaches to causal effect estimation. The bounds, which are often wide in practice, can provide important information about the degree to which causal analyses depend on unverifiable assumptions made by investigators.

Use of the instrumental inequalities in simulated mendelian randomization analyses with coarsened exposures.

Mendelian randomization (MR) requires strong unverifiable assumptions to estimate causal effects. However, for categorical exposures, the MR assumptions can be falsified using a method known as the instrumental inequalities. To apply the instrumental inequalities to a continuous exposure, investigators must coarsen the exposure, a process which can itself violate the MR conditions. Violations of the instrumental inequalities for an MR model with a coarsened exposure might therefore reflect the effect of coarsening rather than other sources of bias. We aim to evaluate how exposure coarsening affects the ability of the instrumental inequalities to detect bias in MR models with multiple proposed instruments under various causal structures. To do so, we simulated data mirroring existing studies of the effect of alcohol consumption on cardiovascular disease under a variety of exposure-outcome effects in which the MR assumptions were met for a continuous exposure. We categorized the exposure based on subject matter knowledge or the observed data distribution and applied the instrumental inequalities to MR models for the effects of the coarsened exposure. In simulations of multiple binary instruments, the instrumental inequalities did not detect bias under any magnitude of exposure outcome effect when the exposure was coarsened into more than 2 categories. However, in simulations of both single and multiple proposed instruments, the instrumental inequalities were violated in some scenarios when the exposure was dichotomized. The results of these simulations suggest that the instrumental inequalities are largely insensitive to bias due to exposure coarsening with greater than 2 categories, and could be used with coarsened exposures to evaluate the required assumptions in applied MR studies, even when the underlying exposure is truly continuous.

Mendelian Randomization With Repeated Measures of a Time-varying Exposure: An Application of Structural Mean Models.

Mendelian randomization (MR) is often used to estimate effects of time-varying exposures on health outcomes using observational data. However, MR studies typically use a single measurement of exposure and apply conventional instrumental variable (IV) methods designed to handle time-fixed exposures. As such, MR effect estimates for time-varying exposures are often biased, and interpretations are unclear. We describe the instrumental conditions required for IV estimation with a time-varying exposure, and the additional conditions required to causally interpret MR estimates as a point effect, a period effect or a lifetime effect depending on whether researchers have measurements at a single or multiple time points. We propose methods to incorporate time-varying exposures in MR analyses based on g-estimation of structural mean models, and demonstrate its application by estimating the period effect of alcohol intake, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol on intermediate coronary heart disease outcomes using data from the Framingham Heart Study. We use this data example to highlight the challenges of interpreting MR estimates as causal effects, and describe other extensions of structural mean models for more complex data scenarios.

Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth.

BACKGROUND: It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants' length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group). RESULTS: Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, -0.93±1.05; prenatal 4200, -1.11±1.12; prenatal 16,800, -0.97±0.97; prenatal 28,000, -1.06±1.07; and prenatal and postpartum 28,000, -0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose. CONCLUSIONS: In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013 .).

Instrumental variable estimation for a time-varying treatment and a time-to-event outcome via structural nested cumulative failure time models.

BACKGROUND: In many applications of instrumental variable (IV) methods, the treatments of interest are intrinsically time-varying and outcomes of interest are failure time outcomes. A common example is Mendelian randomization (MR), which uses genetic variants as proposed IVs. In this article, we present a novel application of g-estimation of structural nested cumulative failure models (SNCFTMs), which can accommodate multiple measures of a time-varying treatment when modelling a failure time outcome in an IV analysis. METHODS: A SNCFTM models the ratio of two conditional mean counterfactual outcomes at time k under two treatment strategies which differ only at an earlier time m. These models can be extended to accommodate inverse probability of censoring weights, and can be applied to case-control data. We also describe how the g-estimates of the SNCFTM parameters can be used to calculate marginal cumulative risks under nondynamic treatment strategies. We examine the performance of this method using simulated data, and present an application of these models by conducting an MR study of alcohol intake and endometrial cancer using longitudinal observational data from the Nurses' Health Study. RESULTS: Our simulations found that estimates from SNCFTMs which used an IV approach were similar to those obtained from SNCFTMs which adjusted for confounders, and similar to those obtained from the g-formula approach when the outcome was rare. In our data application, the cumulative risk of endometrial cancer from age 45 to age 72 under the "never drink" strategy (4.0%) was similar to that under the "always ½ drink per day" strategy (4.3%). CONCLUSIONS: SNCFTMs can be used to conduct MR and other IV analyses with time-varying treatments and failure time outcomes.

The Effect of Maternal Multiple Micronutrient Supplementation on Female Early Infant Mortality Is Fully Mediated by Increased Gestation Duration and Intrauterine Growth.

BACKGROUND: Maternal micronutrient supplementation in pregnancy (MMS) has been shown to improve birth weight among infants in low- and middle-income countries. Recent evidence suggests that the survival benefits of MMS are greater for female infants compared to male infants, but the mechanisms leading to differential effects remain unclear. OBJECTIVE: The objective of this study was to examine the potential mechanisms through which MMS acts on infant mortality among Tanzanian infants. METHODS: We used data collected from pregnant women and newborns in a randomized, double-blind, placebo-controlled trial of MMS conducted in Tanzania to examine mediators of the effect of MMS on 6-wk infant mortality (NCT00197548). Causal mediation analyses with the counterfactual approach were conducted to assess the contributions of MMS on survival via their effects on birth weight, gestational age, weight-for-gestational age, and the joint effect of gestational age and weight-for-gestational age. The weighting method allowed for interaction between gestational age and weight-for-gestational age. RESULTS: Among 7486 newborns, the effect of MMS on 6-wk survival was fully mediated (100%) through the joint effect of gestational age and weight-for-gestational age. MMS was also found to have a significant natural indirect effect through increased birth weight (P-value < 0.001) that explained 75% of the total effect on 6-wk mortality. When analyses were stratified by sex, changes in gestational age and weight-for-gestational age fully mediated the mortality effect among female infants (n = 3570), but these mediators only explained 34% of the effect among males (n = 3833). CONCLUSIONS: The potential sex-specific effects of MMS on mortality may be a result of differences in mechanisms related to birth outcomes. In the context of the Tanzanian trial, the observed effect of MMS on 6-wk mortality for female infants was entirely mediated by increased gestation duration and improved intrauterine growth, while these mechanisms did not appear to be major contributors among male infants.

Lifetime moderate-to-vigorous physical activity and ER/PR/HER-defined post-menopausal breast cancer risk.

PURPOSE: To assess the relationship of moderate-to-vigorous physical activity (MVPA) in leisure-time, household, and occupational domains across the total lifetime and in four age periods with breast cancer risk, as defined by estrogen receptor (ER)/progesterone receptor (PR) status and ER/PR/human epidermal growth factor-2 (HER2) status, among post-menopausal women. METHODS: Data were from 692 women with incident breast cancer and 644 controls in the Canadian Breast Cancer Study, a case-control study of women aged 40-80 years in British Columbia and Ontario. Mean metabolic equivalent (MET)-hours/week for questionnaire-assessed leisure-time, household, and occupational MVPA were calculated for the total lifetime and four age periods (12-17, 18-34, 45-49, and ≥50 years). Odds ratios (ORs) for the relationships between domain-specific MVPA at each lifetime period and risks of ER/PR-defined and ER/PR/HER2-defined breast cancers were estimated using polytomous logistic regression. Trend tests for dose-response relationships were calculated for the ORs across increasing tertiles of mean MET-hours/week of MVPA. RESULTS: Total lifetime leisure-time MVPA was associated with reduced risk of ER-/PR- breast cancer in a dose-response fashion (p trend = 0.014). In contrast, total lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer (p trend < 0.001). When further stratified by HER2 status, the effect of leisure-time MVPA appeared confined to HER2- breast cancers, and the effect of household MVPA did not differ according to HER2 status. Similar trends were observed when stratified by age period. CONCLUSIONS: Lifetime leisure-time MVPA appeared to be associated with reduced risk of ER-/PR-/HER2- breast cancers and lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer, regardless of HER2 status.

Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent.

Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case-control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER-/PR-/HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype.

Risk prediction models for endometrial cancer: development and validation in an international consortium.

BACKGROUND: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. METHODS: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. RESULTS: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). CONCLUSIONS: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Do Early Infant Feeding Practices and Modifiable Household Behaviors Contribute to Age-Specific Interindividual Variations in Infant Linear Growth? Evidence from a Birth Cohort in Dhaka, Bangladesh.

BACKGROUND: Causes of infant linear growth faltering in low-income settings remain poorly understood. Identifying age-specific risk factors in observational studies might be influenced by statistical model selection. OBJECTIVES: To estimate associations of selected household factors and infant feeding behaviors within discrete age intervals with interval-specific changes in length-for-age z-scores (LAZs) or attained LAZ, using 5 statistical approaches. METHODS: Data from a birth cohort in Dhaka, Bangladesh (n = 1157) were analyzed. Multivariable-adjusted associations of infant feeding patterns or household factors with conditional LAZ (cLAZ) were estimated for 5 intervals in infancy. Two alternative approaches were used to estimate differences in interval changes in LAZ, and differences in end-interval attained LAZ and RRs of stunting (LAZ < -2) were estimated. RESULTS: LAZ was symmetrically distributed with mean ± SD = -0.95 ± 1.02 at birth and -1.00 ± 1.04 at 12 mo. Compared with exclusively breastfed infants, partial breastfeeding (difference in cLAZ: -0.11; 95% CI: -0.20, -0.02) or no breastfeeding (-0.30; 95% CI: -0.54, -0.07) were associated with slower growth from 0 to 3 mo. However, associations were not sustained beyond 6 mo. Modifiable household factors (smoking, water treatment, soap at handwashing station) were not associated with infant growth, attained size, or stunting. Alternative statistical approaches yielded mostly similar results as conditional growth models. CONCLUSIONS: The entire infant LAZ distribution was shifted down, indicating that length deficits were mostly caused by ubiquitous or community-level factors. Early-infant feeding practices explained minimal variation in early growth, and associations were not sustained to 12 mo of age. Statistical model choice did not substantially alter the conclusions. Modifications of household hygiene, smoking, or early infant feeding practices would be unlikely to improve infant linear growth in Bangladesh or other settings where growth faltering is widespread.

Effects of Maternal Vitamin D Supplementation During Pregnancy and Lactation on Infant Acute Respiratory Infections: Follow-up of a Randomized Trial in Bangladesh.

BACKGROUND: We examined the effect of maternal vitamin D supplementation during pregnancy and lactation on risk of acute respiratory infection (ARI) in infants up to 6 months of age in Bangladesh. METHODS: This study was nested in a randomized, double-blind, placebo-controlled, 5-arm dose-ranging trial of prenatal and postpartum vitamin D supplementation. One group of women received 0 IU vitamin D per week during pregnancy and for 26 weeks post delivery ("placebo" group), one group received high-dose prenatal vitamin D supplementation of 28 000 IU per week and 26 weeks post delivery, and there were 3 additional dose-ranging groups receiving vitamin D supplementation during pregnancy only (4200, 16 800, and 28 000 IU per week, respectively). Episodes of ARI were identified by active and passive surveillance. The primary outcome was microbiologically confirmed ARI, and the primary analysis compared the high-dose prenatal plus postpartum vitamin D vs placebo groups. RESULTS: In total, 1174 mother-infant pairs were included. Among infants born to mothers in the placebo group, 98% had a venous umbilical cord 25(OH)D level below 30 nmol/L compared with none in the high-dose prenatal plus postdelivery vitamin D group. Incidence of microbiologically confirmed ARI in the high-dose prenatal plus postpartum vitamin D (1.21 episodes per 6 person-months; N = 235) and placebo groups (1.07 episodes per 6 person-months; N = 234) was not significantly different (hazard ratio of 1.12 [95% confidence intervals: 0.90-1.40]). There were no differences in the incidence of microbiologically confirmed or clinical ARI, upper, lower, or hospitalized lower respiratory tract infection between high-dose prenatal plus postpartum vitamin D and placebo groups. CONCLUSIONS: Despite a high prevalence of maternal baseline vitamin D deficiency and significant effects of maternal vitamin D supplementation on infant vitamin D status, the intervention did not reduce the risk of microbiologically confirmed ARI in infants up to 6 months of age.

Determinants of Vitamin D Status of Women of Reproductive Age in Dhaka, Bangladesh: Insights from Husband-Wife Comparisons.

BACKGROUND: Vitamin D deficiency is common among women of reproductive age (WRA) in Bangladesh, but the causes remain unclear. OBJECTIVE: To explain the high prevalence of vitamin D deficiency in WRA in Dhaka, Bangladesh, we compared the vitamin D status of pregnant women with that of their husbands and between pregnant and nonpregnant states. METHODS: This study was an observational substudy of the Maternal Vitamin D for Infant Growth trial conducted in Dhaka, Bangladesh. Women (n = 1300) were enrolled in the second trimester of pregnancy and randomly assigned to 1 of 5 arms consisting of different doses of vitamin D supplements or placebo, with 1 arm continuing supplementation until 6 mo postpartum. A subgroup of trial participants and their husbands with plasma 25-hydroxyvitamin D [25(OH)D] concentration measurements (n = 84), and placebo-group trial participants with serum 25(OH)D measured in the second trimester of pregnancy and 6 mo postpartum (n = 89) were studied using linear mixed-effects regression models. RESULTS: The mean ± SD plasma 25(OH)D in pregnant women in the second trimester was 23 ± 11 nmol/L. Adjusting for age and season, 25(OH)D of pregnant women was 30 nmol/L lower (95% CI: -36, -25 nmol/L) than that of men. Only 9% of total variance in 25(OH)D was explained by factors shared by spousal pairs. Selected nonshared factors (BMI, time spent outdoors, involvement in an outdoor job, sunscreen use) did not explain the association of sex with 25(OH)D. Adjusting for age, season, and BMI, 25(OH)D was similar during pregnancy and 6 mo postpartum (mean difference: -2.4 nmol/L; 95% CI: -5.3, 0.4 nmol/L). CONCLUSIONS: In Dhaka, WRA have substantially poorer vitamin D status than men. Variation in 25(OH)D is not greatly influenced by determinants shared by spouses. Measured nonshared characteristics or pregnancy did not account for the gender differential in 25(OH)D. This trial was registered at clinicaltrials.gov as NCT01924013.

Effect of an integrated neonatal care kit on neonatal health outcomes: a cluster randomised controlled trial in rural Pakistan.

INTRODUCTION: In 2016, 2.6 million children died during their first month of life. We assessed the effectiveness of an integrated neonatal care kit (iNCK) on neonatal survival and other health outcomes in rural Pakistan. METHODS: We conducted a community-based, cluster randomised, pragmatic, open-label, controlled intervention trial in Rahim Yar Khan, Punjab, Pakistan. Clusters, 150 villages and their lady health workers (LHWs), were randomly assigned to deliver the iNCK (intervention) or standard of care (control). In intervention clusters, LHWs delivered the iNCK and education on its use to pregnant women. The iNCK contained a clean birth kit, chlorhexidine, sunflower oil, a continuous temperature monitor (ThermoSpot), a heat reflective blanket and reusable heat pack. LHWs were also given a hand-held scale. The iNCK was implemented primarily by caregivers. The primary outcome was all-cause neonatal mortality. Outcomes are reported at the individual level, adjusted for cluster allocation. Enrolment took place between April 2014 and July 2015 and participant follow-up concluded in August 2015. RESULTS: 5451 pregnant women (2663 and 2788 in intervention and control arms, respectively) and their 5286 liveborn newborns (2585 and 2701 in intervention and control arms, respectively) were enrolled. 147 newborn deaths were reported, 65 in the intervention arm (25.4 per 1000 live births) compared with 82 in the control arm (30.6 per 1000 live births). Neonatal mortality was not significantly different between treatment groups (risk ratio 0.83, 95% CI 0.58 - 1.18; p = 0.30). CONCLUSION: Providing co-packaged interventions directly to women did not significantly reduce neonatal mortality. Further research is needed to improve compliance with intended iNCK use.

New approach for the identification of implausible values and outliers in longitudinal childhood anthropometric data.

PURPOSE: We aimed to demonstrate the use of jackknife residuals to take advantage of the longitudinal nature of available growth data in assessing potential biologically implausible values and outliers. METHODS: Artificial errors were induced in 5% of length, weight, and head circumference measurements, measured on 1211 participants from the Maternal Vitamin D for Infant Growth (MDIG) trial from birth to 24 months of age. Each child's sex- and age-standardized z-score or raw measurements were regressed as a function of age in child-specific models. Each error responsible for a biologically implausible decrease between a consecutive pair of measurements was identified based on the higher of the two absolute values of jackknife residuals in each pair. In further analyses, outliers were identified as those values beyond fixed cutoffs of the jackknife residuals (e.g., greater than +5 or less than -5 in primary analyses). Kappa, sensitivity, and specificity were calculated over 1000 simulations to assess the ability of the jackknife residual method to detect induced errors and to compare these methods with the use of conditional growth percentiles and conventional cross-sectional methods. RESULTS: Among the induced errors that resulted in a biologically implausible decrease in measurement between two consecutive values, the jackknife residual method identified the correct value in 84.3%-91.5% of these instances when applied to the sex- and age-standardized z-scores, with kappa values ranging from 0.685 to 0.795. Sensitivity and specificity of the jackknife method were higher than those of the conditional growth percentile method, but specificity was lower than for conventional cross-sectional methods. CONCLUSIONS: Using jackknife residuals provides a simple method to identify biologically implausible values and outliers in longitudinal child growth data sets in which each child contributes at least 4 serial measurements.

Early childhood linear growth faltering in low-income and middle-income countries as a whole-population condition: analysis of 179 Demographic and Health Surveys from 64 countries (1993-2015).

BACKGROUND: The causes of early childhood linear growth faltering (known as stunting) in low-income and middle-income countries remain inadequately understood. We aimed to determine if the progressive postnatal decline in mean height-for-age Z score (HAZ) in low-income and middle-income countries is driven by relatively slow growth of certain high-risk children versus faltering of the entire population. METHODS: Distributions of HAZ (based on WHO growth standards) were analysed in 3-month age intervals from 0 to 36 months of age in 179 Demographic and Health Surveys from 64 low-income and middle-income countries (1993-2015). Mean, standard deviation (SD), fifth percentiles, and 95th percentiles of the HAZ distribution were estimated for each age interval in each survey. Associations between mean HAZ and SD, fifth percentile, and 95th percentile were estimated using multilevel linear models. Stratified analyses were performed in consideration of potential modifiers (world region, national income, sample size, year, or mean HAZ in the 0-3 month age band). We also used Monte Carlo simulations to model the effects of subgroup versus whole-population faltering on the HAZ distribution. FINDINGS: Declines in mean HAZ from birth to 3 years of age were accompanied by declines in both the fifth and 95th percentiles, leading to nearly symmetrical narrowing of the HAZ distributions. Thus, children with relatively low HAZ were not more likely to have faltered than taller same-age peers. Inferences were unchanged in surveys regardless of world region, national income, sample size, year, or mean HAZ in the 0-3 month age band. Simulations showed that the narrowing of the HAZ distribution as mean HAZ declined could not be explained by faltering limited to a growth-restricted subgroup of children. INTERPRETATION: In low-income and middle-income countries, declines in mean HAZ with age are due to a downward shift in the entire HAZ distribution, revealing that children across the HAZ spectrum experience slower growth compared to the international standard. Efforts to mitigate postnatal linear growth faltering in low-income and middle-income countries should prioritise action on community-level determinants of childhood HAZ trajectories. FUNDING: Bill & Melinda Gates Foundation.

Polymorphisms of Insulin-Like Growth Factor 1 Pathway Genes and Breast Cancer Risk.

Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case-control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs (rs2288378, rs17727841, rs7136446, and rs7956547) were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.