Chris Holmes

Multiomic profiling provides a comprehensive physiological overview at the molecular level, but understanding of its spatiotemporal dynamics remains limited in human populations. We profiled longitudinal whole-blood gene expression and metabolite levels in 335 females over 8 years. Levels of 5061 genes and 181 metabolites changed over time, with individual trajectories often diverging from population-level trends. Longitudinally variable genes showed cell type specificity and enrichment for aging-relevant pathways, including cardiometabolic and neurodegenerative disorders. Longitudinal trajectories were further shaped by genetics, circadian rhythm, seasonality, and environmental pollutant exposures. Integrative analyses revealed extensive static and time-variable cross-omic connectivity. Longitudinal profiling offers insight into the temporal evolution of age-related conditions at the molecular level, and understanding individual variation within these longitudinal patterns will be essential for future precision medicine approaches.

Statistical hypothesis tests typically use prespecified sample sizes, yet data often arrive sequentially. Interim analyses invalidate classical error guarantees, while existing sequential methods require rigid testing preschedules or incur substantial losses in statistical power. We introduce a simple procedure that transforms any fixed-sample hypothesis test into an anytime-valid test while ensuring Type-I error control and near-optimal power with substantial sample savings when the null hypothesis is false. At each step, the procedure predicts the probability that a classical test would reject the null hypothesis at its fixed-sample size, treating future observations as missing data under the null hypothesis. Thresholding this probability yields an anytime-valid stopping rule. In areas such as clinical trials, stopping early and safely can ensure that subjects receive the best treatments and accelerate the development of effective therapies.

The DECOVID database contains harmonized pseudonymized electronic health record (EHR) data on all adult (≥18 years old) patients presenting to two large, digitally mature centers in the United Kingdom between 1 January 2020 and 28 February 2021, with follow-up until at least 28 March 2021. The database was originally developed to support the COVID-19 response but is now available via the PIONEER data hub for researchers to explore a wide range of research questions, including exploratory analyses, risk factor assessment, prediction modeling, and comparative effectiveness studies. Raw data were extracted from local EHRs and transformed into a standardized form (Observational Health Data Sciences and Informatics-Common Data Model version 5.3.1). The database includes 165,420 patients across 256,804 hospital presentations. For these patients, highly granular data are available, including patient demographics, longitudinal vital signs, physiology, treatments, laboratory findings, clinical diagnoses, and outcomes. There are 10,030 patients with COVID-19, of whom 1472 died in hospital.

Multiple sclerosis (MS) affects 2.9 million people. Traditional classification of MS into distinct subtypes poorly reflects its pathobiology and has limited value for prognosticating disease evolution and treatment response, thereby hampering drug discovery. Here we report a data-driven classification of MS disease evolution by analyzing a large clinical trial database (approximately 8,000 patients, 118,000 patient visits and more than 35,000 magnetic resonance imaging scans) using probabilistic machine learning. Four dimensions define MS disease states: physical disability, brain damage, relapse and subclinical disease activity. Early/mild/evolving (EME) MS and advanced MS represent two poles of a disease severity spectrum. Patients with EME MS show limited clinical impairment and minor brain damage. Transitions to advanced MS occur via brain damage accumulation through inflammatory states, with or without accompanying symptoms. Advanced MS is characterized by moderate to high disability levels, radiological disease burden and risk of disease progression independent of relapses, with little probability of returning to earlier MS states. We validated these results in an independent clinical trial database and a real-world cohort, totaling more than 4,000 patients with MS. Our findings support viewing MS as a disease continuum. We propose a streamlined disease classification to offer a unifying understanding of the disease, improve patient management and enhance drug discovery efficiency and precision.

From early in the coronavirus disease 2019 (COVID‐19) pandemic, there was interest in using machine learning methods to predict COVID‐19 infection status based on vocal audio signals, for example, cough recordings. However, early studies had limitations in terms of data collection and of how the performances of the proposed predictive models were assessed. This article describes how these limitations have been overcome in a study carried out by the Turing‐RSS Health Data Laboratory and the UK Health Security Agency. As part of the study, the UK Health Security Agency collected a dataset of acoustic recordings, SARS‐CoV‐2 infection status and extensive study participant meta‐data. This allowed us to rigorously assess state‐of‐the‐art machine learning techniques to predict SARS‐CoV‐2 infection status based on vocal audio signals. The lessons learned from this project should inform future studies on statistical evaluation methods to assess the performance of machine learning techniques for public health tasks.

Composite indicators are useful for summarizing and comparing changes among different communities. The UK Office for National Statistics has created an annual England Health Index (2015–2018) comprised of three main health domains—lives, places, and people—to monitor health over time and across different geographical areas and evaluate the nation’s health. We reviewed the conceptual coherence and statistical requirements, focusing on three main steps: correlation analysis at different levels, comparison of the implemented weights, and a sensitivity and uncertainty analysis. Based on the results, we have highlighted features that have improved the statistical requirements of the forthcoming UK Health Index.

We study the stability of posterior predictive inferences to the specification of the likelihood model and perturbations of the data generating process. In modern big data analyses, useful broad structural judgements may be elicited from the decision-maker but a level of interpolation is required to arrive at a likelihood model. As a result, an often computationally convenient canonical form is used in place of the decision-maker's true beliefs. Equally, in practice, observational datasets often contain unforeseen heterogeneities and recording errors and therefore do not necessarily correspond to how the process was idealised by the decision-maker. Acknowledging such imprecisions, a faithful Bayesian analysis should ideally be stable across reasonable equivalence classes of such inputs. We are able to guarantee that traditional Bayesian updating provides stability across only a very strict class of likelihood models and data generating processes, requiring the decision-maker to elicit their beliefs and understand how the data was generated with an unreasonable degree of accuracy. On the other hand, a generalised Bayesian alternative using the $β$-divergence loss function is shown to be stable across practical and interpretable neighbourhoods, providing assurances that posterior inferences are not overly dependent on accidentally introduced spurious specifications or data collection errors. We illustrate this in linear regression, binary classification, and mixture modelling examples, showing that stable updating does not compromise the ability to learn about the data generating process. These stability results provide a compelling justification for using generalised Bayes to facilitate inference under simplified canonical models.