Search

Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10−6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10−4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.

Magnetic helicity is approximately conserved in resistive MHD models. It quantifies the entanglement of the magnetic field within the plasma. The transport and removal of helicity is crucial in both the dynamo in the solar interior and active region evolution in the solar corona. This transport typically leads to highly inhomogeneous distributions of entanglement.There exists no consistent systematic means of decomposing helicity over varying spatial scales and in localised regions. We apply a multiresolution wavelet decomposition to the magnetic field and demonstrate how it can be applied to various quantities associated with magnetic helicity, including the field line helicity. We use a geometrical definition of helicity which allows these quantities to be calculated for fields with arbitrary boundary conditions. It is shown that the multiresolution decomposition of helicity has the crucial property of local additivity and demonstrate a general linear energy-topology conservation law which is a significant generalisation of the two point correlation decomposition used in the analysis of homogeneous turbulence and periodic fields. The localisation property of the wavelet representation is shown to characterise inhomogeneous distributions which a Fourier representation cannot. Using an analytic representation of a resistive braided field relaxation we demonstrate a clear correlation between the variations in energy at various length scales and the variations in helicity at the same spatial scales. Its application to helicity flows in a surface flux transport model show how various contributions to the global helicity input from active region field evolution and polar field development are naturally separated by this representation., Comment: Submitted to Astronomy and Astrophysics

Magnetic helicity is approximately conserved in resistive MHD models. It quantifies the entanglement of the magnetic field within the plasma. The transport and removal of helicity is crucial in both the dynamo in the solar interior and active region evolution in the solar corona. This transport typically leads to highly inhomogeneous distributions of entanglement.There exists no consistent systematic means of decomposing helicity over varying spatial scales and in localised regions. We apply a multiresolution wavelet decomposition to the magnetic field and demonstrate how it can be applied to various quantities associated with magnetic helicity, including the field line helicity. We use a geometrical definition of helicity which allows these quantities to be calculated for fields with arbitrary boundary conditions. It is shown that the multiresolution decomposition of helicity has the crucial property of local additivity and demonstrate a general linear energy-topology conservation law which is a significant generalisation of the two point correlation decomposition used in the analysis of homogeneous turbulence and periodic fields. The localisation property of the wavelet representation is shown to characterise inhomogeneous distributions which a Fourier representation cannot. Using an analytic representation of a resistive braided field relaxation we demonstrate a clear correlation between the variations in energy at various length scales and the variations in helicity at the same spatial scales. Its application to helicity flows in a surface flux transport model show how various contributions to the global helicity input from active region field evolution and polar field development are naturally separated by this representation., Comment: Submitted to Astronomy and Astrophysics