Inverse-probability weighting and multiple imputation for evaluating selection bias in the estimation of childhood obesity prevalence using data from electronic health records

Background and objectives: Height and weight data from electronic health records are increasingly being used to estimate the prevalence of childhood obesity. Here, we aim to assess the selection bias due to missing weight and height data from electronic health records in children older than five. Methods: Cohort study of 10,811 children born in Navarra (Spain) between 2002 and 2003, who were still living in this region by December 2016. We examined the differences between measured and non-measured children older than 5 years considering weight-associated variables (sex, rural or urban residence, family income and weight status at 2–5 yrs). These variables were used to calculate stabilized weights for inverse-probability weighting and to conduct multiple imputation for the missing data. We calculated complete data prevalence and adjusted prevalence considering the missing data using inverse-probability weighting and multiple imputation for ages 6 to 14 and group ages 6 to 9 and 10 to 14. Results: For 6–9 years, complete data, inverse-probability weighting and multiple imputation obesity age-adjusted prevalence were 13.18% (95% CI: 12.54–13.85), 13.22% (95% CI: 12.57–13.89) and 13.02% (95% CI: 12.38–13.66) and for 10–14 years 8.61% (95% CI: 8.06–9.18), 8.62% (95% CI: 8.06–9.20) and 8.24% (95% CI: 7.70–8.78), respectively. Conclusions: Ages at which well-child visits are scheduled and for the 6 to 9 and 10 to 14 age groups, weight status estimations are similar using complete data, multiple imputation and inverse-probability weighting. Readily available electronic health record data may be a tool to monitor the weight status in children

Pharmacologic sex hormone use before and in early pregnancy in relation to birth and early childhood anthropometric outcomes

Objective: Possible adverse effects resulting from use of hormonal contraceptives have been studied extensively, yet few studies have been conducted evaluating the association between hormonal contraceptive use and offspring anthropometric indices and most studies have been unable to explore formulation-specific effects. Methods: Using data from a large, prospective pregnancy cohort study (n=44,734), with linkage to a national prescription registry, we evaluated the association between use of hormonal contraceptives (defined from dispensed prescription data) prior to and in early pregnancy (characterized by last date of use relative to conception, 12 - >4 months before, 4 - >1 months before, 1 - > 0 months before, and 0-12 weeks after) and preterm birth, small for gestational age, and overweight or obesity at age 3. We characterized use of a hormonal contraception by type (combination oral, progestin-only oral, vaginal ring, transdermal, and injectable) and specific progestin component. Results: We observed a positive association between use of a combination oral contraceptive and preterm birth for all exposure periods (adjusted OR: 1.21, 95% CI: 1.04, 1.41 for exposure within 12 months before conception). Generally, use of other types of hormonal contraception was not associated with preterm birth. Overall, use of a hormonal contraceptive was unrelated to small for gestational age. Evaluation of the association by progestin type identified variation by progestin formulation. We observed a weak, inverse association between early pregnancy use of a combination oral contraceptive and offspring overweight or obesity at age 3 (adjusted OR: 0.75, 95% CI: 0.53, 1.08) and a weak, positive association with use of a progestin-only oral contraceptive in early pregnancy (adjusted OR: 1.26, 95% CI: 0.79, 2.02). Observed associations were robust to sensitivity analyses. Conclusion: Hormonal contraceptive use prior to and in early pregnancy may be associated with preterm birth and offspring overweight. The association appears contingent upon the specific type or progestin component used. The potential for confounding by indication cannot be ruled out. Larger studies using population-based pregnancy cohort data with linkage to prescription registries may offer the potential to explore these questions further.Doctor of Philosoph

Maternal hormonal contraceptive use and offspring overweight or obesity

Experiments in animal models have shown a positive association between in utero exposure to pharmacologic sex hormones and offspring obesity. The developmental effects of such hormones on human obesity are unknown

Factors Associated with Weight Status, Weight Loss and Attrition

This thesis presents four studies which explore factors associated with weight status, weight loss and attrition. The first and second studies, respectively, examine factors associated with weight loss and attrition. The third study utilises statistical methods to detect and correct for sample selection bias on expected weight loss outcomes and the final study examines risk and time preferences in relation to BMI. Overall we identify several variables exhibiting a significant relationship with weight loss and attrition. Further, we identify and correct for non-random sample selection and, in the final research chapter, find some evidence of a relationship between risk preferences and BMI. Whilst the four research chapters presented can be read independently, each chapter builds upon the findings of the previous studies to present a rich and comprehensive assessment of variables of interest, and throughout the thesis we build an increasingly sophisticated methodological approach to the evaluation of weight status, weight loss and attrition. Our research allows for the identification of potential intervention-generated-inequalities, which are of particular importance for both the continuous development of weight management services and policy. For the first time within the current literature we complement a rich, comprehensive assessment of weight management services with sophisticated quantitative methodological approaches and concepts prevalent in the behavioural economics literature but which have rarely been utilised in studies of obesity. Finally, we evidence a requirement to control for sample selection in economic assessments of weight management services to ensure unbiased estimates within cost-benefit and return-on-investment analyses

Internalizing and Externalizing Behavior Problems in Childhood and Early Development of Cardiovascular and Diabetes Risk: A Life Course Perspective

An accumulating evidence-base indicates that internalizing mental health disorders in adulthood are causally associated with cardiovascular diseases (CVD) and type-2 diabetes (T2DM). It is plausible, however, that the relationship between mental and cardiometabolic ill-health becomes established long before adulthood, and that externalizing problems (the other central domain of common psychopathology) are also involved. These questions, as well as questions on the mechanisms that underlie the relationships, have been insufficiently investigated. The overarching goal of this dissertation was to expand current knowledge on how common mental health problems increase cardiometabolic risk over the life course. First, the prospective association between childhood internalizing (emotional problems) and externalizing problems (hyperactivity and conduct problems) with CVD and T2DM risk in adolescence was assessed in data from the Avon Longitudinal Study of Parents and Children (ALSPAC, N=7,730). Results showed that hyperactivity problems were associated with insulin resistance (high HOMA-IR); that hyperactivity and conduct problems were each associated with high triglyceride levels; and that emotional problems were inversely associated with high triglyceride levels. These results suggest that childhood externalizing problems are an early life risk factor for CVD and T2DM and that childhood internalizing problems are not a risk factor or, that risk in these children does not become apparent until after adolescence. Second, the mechanisms underlying the prospective association of childhood hyperactivity and conduct problems with high levels of triglycerides in adolescence were investigated using causal mediation methods. Results showed that despite being associated with hyperactivity and with conduct problems, body mass index and lifestyle health behaviors including sleep, diet, physical activity, alcohol, and smoking, together these variables, as measured, mediated only 19.6 % and 19.3% of the associations of hyperactivity and conduct problems with triglycerides, respectively. These results would suggest that mechanisms other than body adiposity and unhealthy behaviors are also involved and that those mechanisms have a larger role in mediating these relationships. Alternatively, It is possible that the observed small role of health behaviors is due to error in measurement and therefore improving measurements for health behaviors should be a central focus of future work. Third and last, a systematic review of the literature on the relationship between childhood externalizing problems with CVD and T2DM risk was conducted. Studies were graded for propensity to bias. Evidence was summarized and assessed for consistency. Results strongly supported positive associations of externalizing problems with insulin resistance, T2DM, and with increased blood lipids among children and adolescents. Evidence suggested that associations are at least partly independent of body adiposity. Evidence provided mix support for the associations with T2DM and blood lipids in adults and with other outcomes in children or adults. Studies in children tended to be cross-sectional and to use valid and reliable assessment methods, whereas studies of adults tended to be prospective and to rely on less-valid, less reliable assessment methods. These results warrant more research, specifically prospective studies that track children into young adulthood, that employ well-validated measures of externalizing behaviors, that rely on repeated assessments of T2DM and CVD risk throughout follow-up, and that investigate mechanisms other than body adiposity and health behaviors. Overall, this dissertation has found that childhood externalizing problems are prospectively associated with elevated CVD and T2DM risk, specifically with elevated risk of increased levels of blood lipids and insulin resistance. Unlike studies in adults, this dissertation does not support a role of internalizing problems as risk factors. Among children with externalizing problems, risk becomes evident before adolescence and appears to be largely driven by pathways independent of unhealthy behaviors and body adiposity. Implications of this research’s findings for health practice were proposed. This dissertation identified several gaps and methodological shortcoming in the extant literature. Recommendations were made for future research, including fundamental next questions to investigate, and study designs and methodologies that are best suited to tackle those questions

Cognitive function in people with psychiatric and neurological disorders in UK Biobank

Cognitive impairment is a major cause of disability for a large number of working-age adults living with chronic psychiatric and neurological conditions. Although well recognised in schizophrenia spectrum disorders and in neurological diseases such as multiple sclerosis (MS), cognitive impairment has historically received less attention in mood disorders. The relative prevalence of cognitive impairment in bipolar disorder (BD) and major depression compared with other conditions has not been clearly established, and the risk factors that drive cognitive variation within and across conditions are not well understood. The primary focus of this thesis was on BD, and the objectives were: (1) to investigate the prevalence of cognitive impairment in BD, compared with major depression, schizophrenia, MS and Parkinson’s disease (PD); and (2) to develop causal models to quantify and explain variation in cognitive function in BD and in other conditions. The methods encompassed a systematic literature review, a prevalence study using cross-sectional data from the UK Biobank cohort, and a series of multivariable analyses of UK Biobank data using graphical methods, regression- and matching-based estimation, and mediation models. The systematic review indicated that between 5% and 58% of adults with euthymic BD showed cognitive impairment. Prevalence was lower in the mania/BD group identified within the UK Biobank cohort, at around 7-10%, which was similar to rates seen in the MS and PD groups within the cohort. When causal models of cognitive performance in the mania/BD group took account of multiple potential confounders, performance on a short-term visuospatial memory test showed a small but reliable decrement. Mediation models provided evidence of indirect negative effects on cognitive performance via psychotropic medication, but not via cardiometabolic disease. A similar pattern of results was seen in the major depression group, though with smaller effect sizes. This thesis emphasises the importance of cognitive function as a fundamental phenotype in psychiatric and epidemiological research. There is scope to build on this work in future follow-up waves in UK Biobank, as well as in other UK and international cohort studies and through linkage with routine healthcare data

THE OFF-LABEL USE OF ATYPICAL ANTIPSYCHOTICS AND ITS IMPACT ON ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD)

Atypical antipsychotics (AAPs) (also known as second-generation antipsychotics) are the US Food and Drug Administration (FDA) approved medications for schizophrenia, bipolar I disorder, depression and autism. Compared to the typical antipsychotics, AAPs were marketed as reducing adverse side effects such as extrapyramidal symptoms. This resulted in extensive use of AAPs for not only the FDA approved indications but also other conditions that are not approved. However, several post-marketing clinical trials evaluated the use of AAPs and reported serious adverse side effects, including metabolic syndrome, cardiovascular events, or death. The extensive use of AAPs by pediatrics is an important policy problem that imposes serious concerns on public health and economy in the US. A large proportion of total pediatric AAP use is off-label in which the safety and effectiveness are not yet established. Moreover, among the off-label conditions for which AAPs were used, ADHD was the most common primary mental diagnosis. From public health perspective, the risk of type II diabetes in pediatric AAP users was estimated. A retrospective cohort study was conducted and a twice higher risk of developing type II diabetes was estimated for AAP users compared to non-users in pediatrics. From economic efficiency perspective, the cost-effectiveness of AAPs compared to other ADHD medications in pediatric ADHD patients was estimated. Among non-stimulant ADHD medication treatment strategies, AAPs resulted in the lower expected health outcome than other ADHD medications. Also, AAPs were not a favored choice with respect to cost-effectiveness. A comparative effectiveness study that compares resource utilization and costs between atypical antipsychotic (AAP) users and non-AAP users in ADHD revealed that AAP users were likely to visit a healthcare facility for outpatient and inpatient services more frequently than non-AAP users. Total health care costs were significantly higher for AAP users with additional costs of $1,393 (2012 dollars) during six months and$2,784 (2012 dollars) during a year after initiating the AAP treatment