Federated causal inference based on real-world observational data sources:Application to a SARS-CoV-2 vaccine effectiveness assessment

Introduction Causal inference helps researchers and policy-makers to evaluate public health interventions. When comparing interventions or public health programs by leveraging observational sensitive individual-level data from populations crossing jurisdictional borders, a federated approach (as opposed to a pooling data approach) can be used. Approaching causal inference by re-using routinely collected observational data across different regions in a federated manner, is challenging and guidance is currently lacking. With the aim of filling this gap and allowing a rapid response in the case of a next pandemic, a methodological framework to develop studies attempting causal inference using federated cross-national sensitive observational data, is described and showcased within the European BeYond-COVID&nbsp;project. Methods A framework for approaching federated causal inference by re-using routinely collected observational data across different regions, based on principles of legal, organizational, semantic and technical interoperability, is proposed. The framework includes step-by-step guidance, from defining a research question, to establishing a causal model, identifying and specifying data requirements in a common data model, generating synthetic data, and developing an interoperable and reproducible analytical pipeline for distributed deployment. The conceptual and instrumental phase of the framework was demonstrated and an analytical pipeline implementing federated causal inference was prototyped using open-source software in preparation for the assessment of real-world effectiveness of SARS-CoV-2 primary vaccination in preventing infection in populations spanning different countries, integrating a data quality assessment, imputation of missing values, matching of exposed to unexposed individuals based on confounders identified in the causal model and a survival analysis within the matched&nbsp;population. Results The conceptual and instrumental phase of the proposed methodological framework was successfully demonstrated within the BY-COVID project. Different Findable, Accessible, Interoperable and Reusable (FAIR) research objects were produced, such as a study protocol, a data management plan, a common data model, a synthetic dataset and an interoperable analytical&nbsp;pipeline. Conclusions The framework provides a systematic approach to address federated cross-national policy-relevant causal research questions based on sensitive population, health and care data in a privacy-preserving and interoperable way. The methodology and derived research objects can be re-used and contribute to pandemic&nbsp;preparedness.</p

Manning free counterion fraction for a rodlike polyion: Aqueous solutions of short DNA fragments in presence of very low added salt

We quantified the Manning free (uncondensed) counterions fraction θ for dilute aqueous solutions of rodlike polyions: 150 bp DNA fragments, in the presence of a very low concentration of monovalent salt c salt &lt; 0.05 mM. Conductivity measurements of these solutions for DNA base pair concentration range 0.015 c 8 mM were complemented by fluorescence correlation spectroscopy (FCS) measurements of the DNA polyion diffusion coefficient D p (c). We observed a crossover in the normalized conductivity σ (c)/c that nearly halved across the c = 0.05-1 mM range, while D p (c) remained rather constant, as we established by FCS. Analyzing these data we extracted θ (c) = 0.30-0.45, and taking the Manning asymmetry field effect on polyelectrolyte conductivity into account we got θ (c) = 0.40-0.60. We relate the θ(c) variation to gradual DNA denaturation occurring, in the very low salt environment, with the decrease in DNA concentration itself. The extremes of the experimental θ (c) range occur toward the highest, above 1 mM, and the lowest, below 0.05 mM, DNA concentrations and correspond to the theoretical θ values for dsDNA and ssDNA, respectively. Therefore, we confirmed Manning condensation and conductivity models to be valuable in description of dilute solutions of rodlike polyions