Effect of insulin resistance on monounsaturated fatty acid levels : a multi-cohort non-targeted metabolomics and mendelian randomization study

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

High-School Students´ Summer Jobs and their Ensuing Labor Market Achievement : the Long Term Effect

In part because of high and persistent youth unemployment, adolescent students’ transition from school to work is an important policy and research topic. Many countries have implemented public programs offering summer jobs or work while in high-school as measures to smooth the transition. While the immediate effect of the programs on school attendance, school grades, and disposable income is well documented, their effect on the transition to the labor market remains an open question. Observational studies have shown strong positive effects of summer jobs, but also that the estimated effect is highly vulnerable to selection bias. In this paper, some 3700 high-school students applying for summer jobs in the period 1995-2003,via a program, are followed to 30 years of age. A quarter of the applicants were randomly offered a summer job each year. Among the remaining students, 50% had a (non-program related) summer job while in high-school. We find the income, post high-school, for the offered and non-offered groups to be similar and conclude that the effect of summer jobs on the transition to the labor market is inconsequential.

The program and treatment effect of summer jobs on girls’ post-schooling incomes

Public programs (of disputed effect) offering summer jobs or work while in high school to smooth the transition from school to work is commonplace. In this paper, 1447 girls in their first grade of high school between 1997-2003 and randomly allotted summer jobs via a program in Falun (Sweden) are followed 5-12 years after graduation. The program led to a substantially larger accumulation of income while in high school. The causal effect of the high school income on post-schooling incomes was substantial and statistically significant. The implied elasticity of 0.4 is however potentially inflated dueto heterogeneous effects.

Likelihood estimate of treatment effects under selection bias

We consider methods for estimating causal effects of treatment in the situation where the individuals in the treatment and the control group are self selected, i.e., the selection mechanism is not randomized. In this case, simple comparison of treated and control outcomes will not generally yield valid estimates of casual effects. The propensity score method is frequently used for the evaluation of treatment effect. However, this method is based onsome strong assumptions, which are not directly testable. In this paper, we present an alternative modeling approachto draw causal inference by using share random-effect model and the computational algorithm to draw likelihood based inference with such a model. With small numerical studies and a real data analysis, we show that our approach gives not only more efficient estimates but it is also less sensitive to model misspecifications, which we consider, than the existing methods.