Investigating the day-to-day impact of hypoglycaemia in adults with type 1 or type 2 diabetes: design and validation protocol of the Hypo-METRICS application

Introduction: Hypoglycaemia is a frequent adverse event and major barrier for achieving optimal blood glucose levels in people with type 1 or type 2 diabetes using insulin. The Hypo-RESOLVE (Hypoglycaemia—Redefining SOLutions for better liVEs) consortium aims to further our understanding of the day-to-day impact of hypoglycaemia. The Hypo-METRICS (Hypoglycaemia—MEasurement, ThResholds and ImpaCtS) application (app) is a novel app for smartphones. This app is developed as part of the Hypo-RESOLVE project, using ecological momentary assessment methods that will minimise recall bias and allow for robust investigation of the day-to-day impact of hypoglycaemia. In this paper, the development and planned psychometric analyses of the app are described. Methods and analysis: The three phases of development of the Hypo-METRICS app are: (1) establish a working group—comprising diabetologists, psychologists and people with diabetes—to define the problem and identify relevant areas of daily functioning; (2) develop app items, with user-testing, and implement into the app platform; and (3) plan a large-scale, multicountry study including interviews with users and psychometric validation. The app includes 7 modules (29 unique items) assessing: self-report of hypoglycaemic episodes (during the day and night, respectively), sleep quality, well-being/cognitive function, social interactions, fear of hypoglycaemia/hyperglycaemia and work/productivity. The app is designed for use within three fixed time intervals per day (morning, afternoon and evening). The first version was released mid-2020 for use (in conjunction with continuous glucose monitoring and activity tracking) in the Hypo-METRICS study; an international observational longitudinal study. As part of this study, semistructured user-experience interviews and psychometric analyses will be conducted. Ethics and dissemination: Use of the novel Hypo-METRICS app in a multicountry clinical study has received ethical approval in each of the five countries involved (Oxford B Research Ethics Committee, CMO Region Arnhem-Nijmegen, Ethikkommission der Medizinischen Universität Graz, Videnskabsetisk Komite for Region Hovedstaden and the Comite Die Protection Des Personnes SUD Mediterranne IV). The results from the study will be published in peer review journals and presented at national and international conferences. Trial registration number: NCT04304963

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Abstract Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk