Suchergebnisse

No specific funding was received for this study. This manuscript does not reflect opinions or conclusions of any funding agency. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FI, NGF, and NJW were funded by the United Kingdom Medical Research Council Epidemiology Unit core grant (MC_UU_12015/5 and MC_UU_12015/1); NJW, NGF and AK acknowledge National Institute for Health Research (NIHR) Biomedical Research Centre Cambridge (IS-BRC-1215-20014); NJW is an NIHR Senior Investigator; IAB, by the European Union (FP7 and Horizon2020) and the Dutch Scientific Organization (ZonMW); CS, by the Foundation Plan Alzheimer; and AAK, by the NIH training grant (3T32DK007703 and T32CA009001). Alpha Omega Cohort was funded by the Netherlands Heart Foundation (grant 2000T401), the NIH (NIH/ National Heart, Lung, and Blood Institute [NHLBI], and ODS, grant R01HL- 076200), and Unilever R&D, Vlaardingen (margarine production and distribution). The authors acknowledge Kamalita Pertiwi, Wageningen University, the Netherlands, for analyses of data from the Alpha Omega Cohort. Age, Gene/Environment Susceptibility Study Reykjavik was funded by Office of Dietary Supplements, the United States National Institute of Health (NIH) contract N01-AG012100, the National Institute of Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Additional support was provided by the Michael Smith Foundation for Medical Research (#17644) and the Canadian Cancer Society (grant #704735). Chin-Shan Community Cardiovascular Study was funded by Ministry of Science and Technology and National Taiwan University, Taiwan (MOST 103-2314-B-002 -135 –MY3, NSC 100-2314-B-002 -113 –MY3, NTUH 105-S3120, NTUH 106-S3453). The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, ...

BACKGROUND: Instrumental variable methods can estimate the causal effect of an exposure on an outcome using observational data. Many instrumental variable methods assume that the exposure-outcome relation is linear, but in practice this assumption is often in doubt, or perhaps the shape of the relation is a target for investigation. We investigate this issue in the context of Mendelian randomization, the use of genetic variants as instrumental variables. METHODS: Using simulations, we demonstrate the performance of a simple linear instrumental variable method when the true shape of the exposure-outcome relation is not linear. We also present a novel method for estimating the effect of the exposure on the outcome within strata of the exposure distribution. This enables the estimation of localized average causal effects within quantile groups of the exposure or as a continuous function of the exposure using a sliding window approach. RESULTS: Our simulations suggest that linear instrumental variable estimates approximate a population-averaged causal effect. This is the average difference in the outcome if the exposure for every individual in the population is increased by a fixed amount. Estimates of localized average causal effects reveal the shape of the exposure-outcome relation for a variety of models. These methods are used to investigate the relations between body mass index and a range of cardiovascular risk factors. CONCLUSIONS: Nonlinear exposure-outcome relations should not be a barrier to instrumental variable analyses. When the exposure-outcome relation is not linear, either a population-averaged causal effect or the shape of the exposure-outcome relation can be estimated. ; The EPIC-InterAct study received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). ; This is the final published version. It first appeared at http://journals.lww.com/epidem/pages/articleviewer.aspx?year=2014&issue=11000&article=00014&type=abstract.

BACKGROUND: Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach. METHODS: Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes. FINDINGS: All four SNPs were associated with 25(OH)D concentrations (p0·25). INTERPRETATION: The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes. FUNDING: UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme. ; This is the final published version. It is available from Elsevier in The Lancet Diabetes & Endocrinology here: http://www.sciencedirect.com/science/article/pii/S2213858714701846.