Reducing the Probability of False Positive Research Findings by Pre-Publication Validation - Experience with a Large Multiple Sclerosis Database

*Objective*
We have assessed the utility of a pre-publication validation policy in reducing the probability of publishing false positive research findings. 
*Study design and setting*
The large database of the Sylvia Lawry Centre for Multiple Sclerosis Research was split in two parts: one for hypothesis generation and a validation part for confirmation of selected results. We present case studies from 5 finalized projects that have used the validation policy and results from a simulation study.
*Results*
In one project, the "relapse and disability" project as described in section II (example 3), findings could not be confirmed in the validation part of the database. The simulation study showed that the percentage of false positive findings can exceed 20% depending on variable selection. 
*Conclusion*
We conclude that the validation policy has prevented the publication of at least one research finding that could not be validated in an independent data set (and probably would have been a "true" false-positive finding) over the past three years, and has led to improved data analysis, statistical programming, and selection of hypotheses. The advantages outweigh the lost statistical power inherent in the process

Uncertainty with varying subsurface permeabilities reduced using coupled Random Field and extended Theory of Porous Media contaminant transport models

To maximize the usefulness of groundwater flow models for the protection of aquifers and abstraction wells, it is necessary to identify and decrease the uncertainty associated with the major parameters such as permeability. To do this, there is a need to develop set of estimates representing subsurface heterogeneity or representative soil permeability estimates. Here, we use a coupled Random Field and extended Theory of Porous Media (eTPM) simulation to develop a robust model with a good predictive ability that reduces uncertainty. The coupled model is then validated with a physical sandbox experiment. Uncertainty is reduced by using 500 realisations of the permeability parameter using the eTPM approach. A multi-layer contaminant transport scenario with varying permeabilities, similar to what could be expected with shallow alluvial sediments, is simulated. The results show that the contaminant arrival time could be strongly affected by random field realizations of permeability compared with a modelled homogenous permeability parameter. The breakthrough time for heterogeneous permeabilities is shorter than the homogeneous condition. Using the 75% confidence interval (CI), the average contaminant concentration shows 4.4% variation from the average values of the considered area and 8.9% variation in the case of a 95% confidence interval.European Union’s Horizon 2020 Programm

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02–1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04–1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09–1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation