Efficient targeted learning of heterogeneous treatment effects for multiple subgroups

In biomedical science, analyzing treatment effect heterogeneity plays an essential role in assisting personalized medicine. The main goals of analyzing treatment effect heterogeneity include estimating treatment effects in clinically relevant subgroups and predicting whether a patient subpopulation might benefit from a particular treatment. Conventional approaches often evaluate the subgroup treatment effects via parametric modeling and can thus be susceptible to model mis-specifications. In this paper, we take a model-free semiparametric perspective and aim to efficiently evaluate the heterogeneous treatment effects of multiple subgroups simultaneously under the one-step targeted maximum-likelihood estimation (TMLE) framework. When the number of subgroups is large, we further expand this path of research by looking at a variation of the one-step TMLE that is robust to the presence of small estimated propensity scores in finite samples. From our simulations, our method demonstrates substantial finite sample improvements compared to conventional methods. In a case study, our method unveils the potential treatment effect heterogeneity of rs12916-T allele (a proxy for statin usage) in decreasing Alzheimer's disease risk.     

Cox proportional hazards models with left truncation and time‐varying coefficient: Application of age at event as outcome in cohort studies

When analyzing time‐to‐event cohort data, two different ways of choosing a time scale have been discussed in the literature: time‐on‐study or age at onset of disease. One advantage of choosing the latter is interpretability of the hazard ratio as a function of age. To handle the analysis of age at onset in a principled manner, we present an analysis of the Cox Proportional Hazards model with time‐varying coefficient for left‐truncated and right‐censored data. In the analysis of Northern Manhattan Study (NOMAS) with age at onset of stroke as outcome, we demonstrate that well‐established risk factors may be important only around a certain age span and less established risk factors can have a strong effect in a certain age span.     

First nationwide survey of prevalence of overweight, underweight, and abdominal obesity in Iranian adults

Objective: The goal was to estimate the prevalence of overweight, obesity, underweight, and abdominal obesity among the adult population of Iran. Research Methods and Procedures: A nationwide cross‐sectional survey was conducted from December 2004 to February 2005. The selection was conducted by stratified probability cluster sampling through household family members in Iran. Weight, height, and waist circumference (WC) of 89,404 men and women 15 to 65 years of age (mean, 39.2 years) were measured. The criteria for underweight, normal‐weight, overweight, and Class I, II, and III obesity were BMI <18.5, 18.5 to 24.9, 25 to 29.9, 30 to 34.9, 35 to 39.9, and ≥40 (kg/m²), respectively. Abdominal obesity was defined as WC ≥102 cm in men and ≥88 cm in women. Results: The age‐adjusted means for BMI and WC were 24.6 kg/m² in men and 26.5 kg/m² in women and 86.6 cm in men and 89.6 cm in women, respectively. The age‐adjusted prevalence of overweight or obesity (BMI ≥25) was 42.8% in men and 57.0% in women; 11.1% of men and 25.2% of women were obese (BMI ≥30), while 6.3% of men and 5.2% of women were underweight. Age, low physical activity, low educational attainment, marriage, and residence in urban areas were strongly associated with obesity. Abdominal obesity was more common among women than men (54.5% vs. 12.9%) and greater with older age. Discussion: Excess body weight appears to be common in Iran. More women than men present with overweight and abdominal obesity. Prevention and treatment strategies are urgently needed to address the health burden of obesity.     

Assessment of obesity stigmatization in children and adolescents: modernizing a standard measure

Objective: Stigmatization of overweight children is highly prevalent. However, the measurement of stigma has varied widely across studies. An up‐to‐date version of a commonly used measure of weight‐related stigma is needed. Research Methods and Procedures: Poser 5 (DAZ software) was used to develop 12 modernized figures, using three‐dimensional models rendered as high‐resolution images. They depicted one overweight, one non‐overweight, and four disabled children of each sex. Children recruited from public and private schools (N = 261; mean age, 11.3 years; median BMI z‐score = 0.33; 77.0% white, 11.5% Asian, and 7.7% Maori) ranked these figures in order of liking. Participants also ranked traditionally used line drawings depicting comparable images. Participants rated each new figure on measures of liking and stereotypical attributes on 100‐mm visual analog scales (VASs). Results: Rankings of liking of the new figures were highly correlated with rankings of corresponding old figures, especially for overweight figures [boys: ρ (77) = 0.72, p < 0.001; girls: ρ (153) = 0.68, p < 0.001]. Rankings of overweight and other figures were also highly correlated with VAS assessment of liking and with a composite, internally consistent VAS measure of liking and stereotypical attributes. Only negative stereotypes about the intelligence of overweight boys and girls contributed significantly to the variance in liking. Discussion: An updated and modernized tool for assessing children's weight stigma was developed and its construct validity supported. The present findings suggest that stereotypes about low intelligence may contribute to weight stigma among children. More research is needed on the causes and components of weight stigma so that it can be effectively reduced.     

Lifetime weight patterns in male physicians: the effects of cohort and selective survival

Objective: The natural history of lifetime weight change is not well understood because of conflicting evidence from cross‐sectional and longitudinal studies. Cross‐sectional analyses find that adult weight is highest at ～60 years of age and lower thereafter. Longitudinal analyses have not found this pattern. Our objective was to test whether cohort effects and selective survival may explain the differences observed between cross‐sectional and longitudinal studies. Research Methods and Procedures: We analyzed data on white men from the Johns Hopkins Precursors Study (n = 1197). Weight and height were measured at enrollment during medical school. The Precursors Study collected subsequent weight measurements by self‐report and follows all participants for mortality. Results: In preliminary analyses that ignored cohort and survival effects, average weight increased 0.16 kg/yr to age 65 (p < 0.001) and declined 0.10 kg/yr thereafter (p = 0.002). When controlling for differing rates of weight change by cohort and survival group, the apparent decline after 65 years of age was mostly explained. Discussion: These data suggest that, in white men, weight increases steadily until age 65 and then plateaus. These findings emphasize the necessity of longitudinal rather than cross‐sectional data to describe lifetime weight patterns.     

Prevalence of Pre‐obesity and Obesity in Urban Adult Mexicans in Comparison with Other Large Surveys

Objective: 1. To estimate the prevalence of pre‐obesity and obesity in a 1992 to 1993 national survey of the Mexican urban adult population. 2. To compare our findings with other national surveys and with data for Mexican Americans. Research Methods and Procedures: The national representative sample of the Mexican urban adult population included 8462 women and 5929 men aged 20 to 69 years from 417 towns of >2500 people. Body mass index (BMI), calculated from measured weight and height, was classified using the World Health Organization categories of underweight (BMI < 18.5 kg/m²), normal weight (BMI 18.5 to 24.9 kg/m²), pre‐obesity (PreOB = BMI 25 to 29.9 kg/m²) and obesity (OB = BMI 30+ kg/m²). Estimates for Mexican Americans were calculated from U.S. survey data. Results: Overall, 38% of the Mexican urban adult population were classified as pre‐obese and 21% as obese. Men had a higher prevalence of pre‐obesity than women did at all ages, but women had higher values of obesity. Both pre‐obesity and obesity increased with age up to the age range brackets of 40 to 49 or 50 to 59 years for both men and women. Both pre‐obesity and obesity prevalence estimates were remarkably similar to data for Mexican Americans from 1982 through 1984. Comparison with other large surveys showed that countries differed more in the prevalence of obesity than of pre‐obesity, leading to differences in the PreOB/OB ratio, and that countries also differed in the gender ratio (female/male) for both pre‐obesity and obesity. Discussion: Pre‐obesity and obesity were high in our population and increased with age. Our approach of characterizing large surveys by PreOB/OB and gender ratios appeared promising.     

Heterogeneity in place effects on health: The case of time preferences and adolescent obesity

We leverage a natural experiment in combination with data on adolescents’ time preferences to assess whether there is heterogeneity in place effects on adolescent obesity. We exploit the plausibly exogenous assignment of military servicemembers, and consequently their children, to different installations to identify place effects. Adolescents’ time preferences are measured by a validated survey scale. Using the obesity rate in the assigned installation county as a summary measure of its obesity-related environments, we show that exposure to counties with higher obesity rates increases the likelihood of obesity among less patient adolescents but not among their more patient counterparts.     

Effects of dietary lactose on long-term high-fat-diet-induced obesity in rats

Objective: In this study, we examined the effects of lactose on long‐term high‐fat‐diet‐induced obesity in rats. Research Methods and Procedures: A total of 112 Sprague‐Dawley strain female rats (6 weeks old) were divided into four groups: a basic control diet group (Cont), 10% lactose diet group (Lac), high‐fat diet group (Fat), and high‐fat with 10% lactose diet group (Fat+Lac). After 0, 7, 14, and 84 days from starting the experimental diet, the animals were fasted overnight and killed by bleeding from the abdominal aorta under anesthesia (n = 8 or 9/group). Results: After 84 days, the addition of lactose to the high‐fat diet decreased the final body weight, body weight gain, fat accumulation, and the levels of serum leptin, serum triglycerides, and serum glucose significantly (p < 0.05). Although there was no significant difference in the levels of serum calcium and phosphorus between the Fat and Fat+Lac groups, lumbar vertebral bone mineral density was significantly higher in the Fat+Lac group than in the Cont group on Day 82. Interestingly, the level of serum 1α, 25‐dihydroxyvitamin D₃ in the Fat+Lac group on Day 84 was reduced by 74% compared with the Fat group (p < 0.01), while there was no significant difference in serum parathyroid hormone levels between the Fat and Fat+Lac groups. Discussion: This is the first study to suggest that the addition of lactose to a long‐term high‐fat diet may regulate not only calcium metabolism but also fat deposition. Further studies on the mechanism of dietary lactose in the regulation of adiposity would provide valuable data for the prevention of long‐term high‐fat‐diet‐induced obesity.     

落叶松针叶内缩合单宁含量与树龄及家系的关系

为了研究树龄、家系和生长时期对落叶松组成抗性的影响,在7和8月采集落叶松针叶,对比分析了长白73-26(Larix olgensis 73-26)和73-28(L.olgensis 73-28),杂种日5×兴9(L.kaempferi 5×L.gmelinii9)和日3×兴2(L.kaempferi 3×L.gmelinii2)4个家系的不同年龄落叶松针叶内缩合单宁含量。结果表明:落叶松针叶内缩合单宁含量,受树龄×家系,树龄×家系×生长时期的交互效应影响差异显著。在幼龄林、中龄林和近熟林3个年龄等级中,幼龄林显著高于其他林龄,在4个家系中,杂种家系显著高于长白家系;同时,在落叶松生长旺盛的7月显著高于生长缓慢的8月,说明落叶松在7月组成抗性相对较强,幼龄林和杂种家系的组成抗性相对较强。因此,建议多种植抗性较强的杂种落叶松,同时在8月以后加强对中龄和近熟林木的防虫监护。     

Changes in BMI and the prevalence of overweight and obesity in children and adolescents in Cracow, Poland, 1971–2000

The aim of this study is to examine changes in prevalence of overweight and obesity, using International Obesity Task Force criteria, in three cohorts of children and youth living in Cracow, Poland, in 1971, 1983 and 2000. Rates of overweight and obesity doubled among boys and girls, from 7.5% and 6.5% in 1971, to 15.2% and 11.8% in the year 2000. The greatest increases in prevalence occurred in the youngest age groups (7–12 years for boys and 7–10 years for girls), increases being less extensive among adolescents, and lowest of all in the oldest age groups (16–18 years in boys and 14–18 years in girls). The absence of a positive secular trend in BMI among adolescent females relative to males may be due to sociocultural pressures associated with transition to a free market economy in Poland. The extent to which girls attempt to achieve the ideal body, as portrayed by media and society more generally, increases across adolescence.     

Small rodent population fluctuations: The effects of age structure and seasonality

Despite more than 50 years of effort, the causes and mechanisms of small rodent population fluctuations remain unknown. The two major questions are as follows: (1) what is the cause of population decline and (2) what is the cause of cyclicity and its geographical variation? At present, no hypothesis can provide answers to both these questions. Recently, progress has been made by Boonstra (1994), who proposed the senescence hypothesis to explain the cause of cyclic decline in population numbers. Here, we tested the main prediction that voles in decline are older than in other phases of the cycle, by analysing changes in age structure in a fluctuating population of the bank vole (Clethrionomys glareolus). The results generally support this prediction; however, the differences in absolute age seem to be too small to explain the occurrence of senescent animals exclusively in declines. We propose a new model to explain changes in age structure and the mechanisms behind the decline and geographic variation in cyclicity. It is based on the idea that voles are oldest in declines, developed independently of Boonstra. However, it differs in three respects: (1) it is more general and thereby applicable to the whole cycle; (2) density-dependent changes in age structure are based on the bimodality in a female's age at first reproduction; and (3) it stresses developmental rather than physiological changes in the quality of decline of animals as being relevant to the rate of senescence. We propose that seasonality of the environment is a principal candidate to explain geographical variation in cyclicity. We present substantial theoretical and empirical evidence to indicate that in more seasonal environments with shortened vegetation periods, population dynamics is inevitably less stable due to increased variation in two critical parameters – age at first reproduction and the length of the breeding season – which determine population growth rates. Any external perturbation may then easily destabilize population numbers. The general applicability of the seasonality-senescence hypothesis to other mammalian species decreases with declining r and increasing life span. The hypothesis is falsifiable, and testable predictions are provided.     

The short-term and long-term effects of parental age in the bean weevil (Acanthoscelides obtectus)

We examined the influence of parental age on life history traits of their offspring in the lines of bean weevil that have evolved different rates of senescence. Measurements included preadult traits (egg size, embryonic developmental time, total preadult developmental time, preadult viability) and adult traits (body weight, total realized fecundity of females, first day of egg laying, early fecundity, late fecundity and longevity). The negative parental age effects were observed for all traits except for the early and total realized fecundity. We did not detect statistically significant line×parental age interactions for either preadult- or adult-survival, so offspring survival did not change with parental age after selection for early vs. late reproduction. It seems that selection acting on the quality of offspring produced by parents of different ages has not been responsible for the evolution of senescence in bean weevil. This revised version was published online in August 2006 with corrections to the Cover Date.     

Maternal BMI and country of birth as indicators of childhood obesity in children of Mexican origin

Objective: The goal of this study was to evaluate the relationship between maternal and childhood BMI at baseline in a group of 5‐ to 18‐year‐old children and their mothers, all of whom were of Mexican origin, low socioeconomic status, and enrolled in a cohort study in Houston, TX. Research Methods and Procedures: Using data from 438 mother‐child dyads residing in the same household, we completed logistic regression analyses to determine maternal factors associated with the child being overweight or at‐risk‐for‐overweight, after adjusting for the child's gender, age, and level of physical activity and other maternal confounders. Results: Almost one‐half of the boys and girls (47% and 44%, respectively) were either overweight or at‐risk‐for‐overweight. Obese mothers were twice as likely to have an overweight and/or at‐risk‐for‐overweight child compared with normal‐weight mothers. Women born in the U.S. were twice as likely to have an overweight and/or at‐risk‐for‐overweight child compared with women born in Mexico. In addition, women with less than a high school education were twice as likely to have an overweight child compared with their more educated peers. Discussion: The high prevalence of overweight or at‐risk‐for‐overweight among Mexican‐origin children of low socioeconomic status suggests a continued need to develop and implement culturally sensitive preventive interventions for this minority population. Our data also suggest a need to tailor such interventions particularly for children of obese mothers and those born in the U.S.     

太白红杉生殖年龄及其影响因素分析

研究了太白红杉的平均生殖年龄、最高生殖年龄和最小生殖年龄以及与环境之间的关系。结果表明太白红杉的平均生殖年龄为78．59a,最小生殖年龄为26a,最大生殖年龄为208a;其中南坡太白山最小生殖年龄26a、最高生殖年龄153a、平均生殖年龄72．97a;北坡最小生殖年龄29a、最高生殖年龄208a、平均生殖年龄92a。海拔和年降水与平均生殖年龄呈正相关,坡度与最高生殖年龄呈正相关,最高生殖年龄与最小生殖年龄呈正相关,表明提早生殖会减少太白红杉的生殖寿命。     

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

This study sought to find more exon mutation sites and lncRNA candidates associated with type 2 diabetes mellitus (T2DM) patients with obesity (O‐T2DM). We used O‐T2DM patients and healthy individuals to detect mutations in their peripheral blood by whole‐exon sequencing. And changes in lncRNA expression caused by mutation sites were studied at the RNA level. Then, we performed GO analysis and KEGG pathway analysis. We found a total of 277 377 mutation sites between O‐T2DM and healthy individuals. Then, we performed a DNA‐RNA joint analysis. Based on the screening of harmful sites, 30 mutant genes shared in O‐T2DM patients were screened. At the RNA level, mutations of 106 differentially expressed genes were displayed. Finally, a consensus mutation site and differential expression consensus gene screening were performed. In the current study, the results revealed significant differences in exon sites in peripheral blood between O‐T2DM and healthy individuals, which may play an important role in the pathogenesis of O‐T2DM by affecting the expression of the corresponding lncRNA. This study provides clues to the molecular mechanisms of metabolic disorders in O‐T2DM patients at the DNA and RNA levels, as well as biomarkers of the risk of these disorders.     

The effects of mass and age on standard metabolic rate in house crickets

Abstract. This study employed flow-through respirometry to measure the oxygen consumption rates (VO₂) of inactive male house crickets, Acheta domesticus L. (Orthoptera: Gryllidae), and to quantify the effects of body mass and adult age on standard metabolic rate (SMR). The Vo₂ increased with male body mass at a rate similar to that found in other studies of insect aerobic metabolism. The data reported in this study are combined with published data from other species of Orthoptera to generate a consensus allometric relationship between SMR and body mass for the Order. In general, the Orthoptera expend 2–3 times the energy per unit of body mass when inactive as compared to other arthropods, such as tenebrionid beetles, ants and spiders. Possible explanations for this substantial difference are discussed. By contrast to body mass, mass-specific Vo₂ decreased with increasing male age. This age effect has previously been reported for mammals but is not well established for insects, and its implications for the preference of cricket females for older mates is discussed. As energy expended for metabolic maintenance comprises 78% of a male cricket's daily energy budget, changes in SMR may have a substantial effect on the energy available for reproduction.