Multidisciplinary ecosystem to study lifecourse determinants and prevention of early-onset burdensome multimorbidity (MELD-B) – protocol for a research collaboration

Background: Most people living with multiple long-term condition multimorbidity (MLTC-M) are under 65 (defined as ‘early onset’). Earlier and greater accrual of long-term conditions (LTCs) may be influenced by the timing and nature of exposure to key risk factors, wider determinants or other LTCs at different life stages. We have established a research collaboration titled ‘MELD-B’ to understand how wider determinants, sentinel conditions (the first LTC in the lifecourse) and LTC accrual sequence affect risk of early-onset, burdensome MLTC-M, and to inform prevention interventions. Aim: Our aim is to identify critical periods in the lifecourse for prevention of early-onset, burdensome MLTC-M, identified through the analysis of birth cohorts and electronic health records, including artificial intelligence (AI)-enhanced analyses. Design: We will develop deeper understanding of ‘burdensomeness’ and ‘complexity’ through a qualitative evidence synthesis and a consensus study. Using safe data environments for analyses across large, representative routine healthcare datasets and birth cohorts, we will apply AI methods to identify early-onset, burdensome MLTC-M clusters and sentinel conditions, develop semi-supervised learning to match individuals across datasets, identify determinants of burdensome clusters, and model trajectories of LTC and burden accrual. We will characterise early-life (under 18 years) risk factors for early-onset, burdensome MLTC-M and sentinel conditions. Finally, using AI and causal inference modelling, we will model potential ‘preventable moments’, defined as time periods in the life course where there is an opportunity for intervention on risk factors and early determinants to prevent the development of MLTC-M. Patient and public involvement is integrated throughout

Quantum dynamics of the corner of the Bianchi IX model in WKB approximation

In this paper we analyse the Bianchi IX Universe dynamics within the corner region associated to the potential term which the spatial curvature induces in the Minisuperspace. The study is done in the vacuum and in the presence of a massless scalar field $\phi$ and a cosmological constant term $\Lambda$. We investigate the dynamics in terms of WKB scenario for which the isotropic Misner variables (the volume) and one of the two anisotropic ones (and $\phi$ when present) are treated on a semi-classical level, while the remaining anisotropy degree of freedom, the one trapped in the corner, is described on a pure quantum level. The quantum dynamics always reduces to the one of a time-dependent Schr\"{o}edinger equation for a harmonic potential with a time dependent frequency. The vacuum case is treated in the limits of a collpasing and an expanding Universe, while the dynamics in presence of $\phi$ and $\Lambda$ is studied for $t \rightarrow \infty$. In both analysis the quantum dynamics of the anisotropy variable is associated to a decaying standard deviation of its probability density, corresponding to a suppression of the quantum anisotropy associated. In the vacuum case, the corner configuration becomes an attractor for the dynamics and the evolution resembles that one of a Taub cosmology in the limit of a non-singular initial Universe. This suggests that if the Bianchi dynamics enters enough the potential corner then the initial singularity is removed and a Taub picture emerges. The case when $\phi$ is present well mimics the De-Sitter phase of an inflationary Universe. Here we show that both the classical and quantum anisotropies are exponentially suppressed, so that the resulting dynamics corresponds to an isotropic closed Robertson-Walker geometry.Comment: 9 pages, 3 figures. Updated bibliography and corrected typo

Quantum dynamics of the corner of the Bianchi IX model in WKB approximation

In this paper we analyze the Bianchi IX Universe dynamics within the corner region associated to the potential term which the spatial curvature induces in the minisuperspace. We investigate the dynamics in terms of the WKB scenario: the isotropic Misner variable (α) and one of the two anisotropic variables (β+) are treated as semiclassical, while the remaining anisotropy (β−) is described on a pure quantum level. The quantum dynamics always reduces to the one of a time-dependent Schrödinger equation for a harmonic potential with a time dependent frequency. The study is done in the vacuum and in the presence of a massless scalar field ϕ and a cosmological constant term Λ. The vacuum case is treated in the limits of a collapsing and an expanding Universe, while the dynamics in presence of ϕ and Λ is studied only for t→∞. In both analyses the quantum dynamics of the anisotropy variable β− suggests a suppression of the quantum anisotropy associated. In the vacuum case the corner configuration becomes an attractor for the dynamics and the evolution resembles that of a Taub cosmology in the limit of a nonsingular initial Universe. This suggests that if the Bianchi dynamics enters deeply enough in the potential corner the initial singularity is removed and a Taub picture emerges. The case when ϕ is present well mimics the de Sitter phase of an inflationary Universe. Here we show that both the classical and quantum anisotropies are exponentially suppressed and therefore the resulting dynamics corresponds to an isotropic closed Robertson-Walker geometry

Fat inflatons, large turns and the η-problem

It is commonly believed that a successful period of inflation driven by a single or several scalar fields requires a specific hierarchy of masses given by $M_{inf}\ll H \ll M_{heavy}$, where $M_{inf}$ can correspond to several or a single light field and $M_{heavy}\,\,\,$ corresponds to any heavy field that might be integrated out if it satisfies suitable conditions. This is at the heart of the so called $\eta$-problem in inflation, since large contributions to the masses of the inflatons might spoil the slow-roll conditions required for inflation. We show that, while this is an unavoidable conclusion in single field inflation, in multifield inflation, heavy fields as defined above, may be fully responsible for a successful period of what we call fat slow-roll inflation. Moreover we show that in this scenario, the turning rate of the inflationary trajectory, $\Omega/H$, is larger than one. Thus, the $\eta$-problem is evaded with large turns in fat inflation. Depending on the perturbations' mass spectra, cosmological predictions will differ either slightly or largely with respect to those of the single field case. We illustrate this scenario in a concrete example in Type IIB string flux compactifications, where a probe D5-brane moving along the angular and radial directions in a warped throat drives fat D5-brane natural inflation. An instantaneous superplanckian decay constant can be defined, consistent with our low energy approximations, thanks to the strong warping of the geometry. We compute the cosmological observables, which differ from the single field case. We also discuss fat inflation in the context of recently proposed swampland de Sitter conjectures.Comment: 41 pages, 13 figures. Minor typos fixed, references added, appendix A expanded. To appear in JCA

Mapping domains of early-life determinants of future multimorbidity across three UK longitudinal cohort studies

Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early-life determinants of multimorbidity can be characterised across three UK cohort studies.We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early-life variables that fit into 12 domains of early-life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups.The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain.Conceptualising the risk of future multimorbidity as lifecourse domains composed of multiple factors can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity

Cohort profile for the creation of the SAIL MELD-B e-cohort (SMC) and SAIL MELD-B children and Young adult e-cohort (SMYC)

Purpose: we have established the SAIL MELD-B electronic cohort (e-cohort SMC) and the SAIL MELD-B children and Young adults e-cohort (SMYC) as a part of the Multidisciplinary Ecosystem to study Lifecourse Determinants and Prevention of Early-onset Burdensome Multimorbidity (MELD-B) project. Each cohort has been created to investigate and develop a deeper understanding of the lived experience of the ‘burdensomeness’ of multimorbidity by identifying new clusters of burdensomeness indicators, exploring early life risk factors of multimorbidity and modelling hypothetical prevention scenarios.Participants: the SMC and SMYC are longitudinal e-cohorts created from routinely-collected individual-level population-scale anonymised data sources available within the Secure Anonymised Information Linkage (SAIL) Databank. They include individuals with available records from linked health and demographic data sources in SAIL at any time between 1st January 2000 and 31st December 2022. The SMYC e-cohort is a subset of the SMC, including only individuals born on or after the cohort start date.Findings to date: the SMC and SMYC cohorts include 5,180,602 (50.3% female and 49.7% male) and 896,155 (48.7% female and 51.3% male) individuals respectively. Considering both primary and secondary care health data, the five most common long-term conditions for individuals in SMC are ‘Depression’, affecting 21.6% of the cohort, ‘Anxiety’ (21.1%), ‘Asthma’ (17.5%), ‘Hypertension’ (16.2%) and ‘Atopic Eczema’ (14.1%), and the five most common conditions for individuals in SMYC are ‘Atopic Eczema’ (21.2%), ‘Asthma’ (11.6%), ‘Anxiety’ (6.0%), ‘Deafness’ (4.6%) and ‘Depression’ (4.3%).Future plans: the SMC and SMYC e-cohorts have been developed using a reproducible, maintainable concept curation pipeline, which allows for the cohorts to be updated dynamically over time and manages for the request and processing of further approved long-term conditions and burdensomeness indicators extraction. Best practices from the MELD-B project can be utilised across other projects, accessing similar data with population-scale data sources and trusted research environments