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 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 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 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 preparedness.

Characterization of cassava ORANGE proteins and their capability to increase provitamin A carotenoids accumulation.

Cassava (Manihot esculenta Crantz) biofortification with provitamin A carotenoids is an ongoing process that aims to alleviate vitamin A deficiency. The moderate content of provitamin A carotenoids achieved so far limits the contribution to providing adequate dietary vitamin A levels. Strategies to increase carotenoid content focused on genes from the carotenoids biosynthesis pathway. In recent years, special emphasis was given to ORANGE protein (OR), which promotes the accumulation of carotenoids and their stability in several plants. The aim of this work was to identify, characterize and investigate the role of OR in the biosynthesis and stabilization of carotenoids in cassava and its relationship with phytoene synthase (PSY), the rate-limiting enzyme of the carotenoids biosynthesis pathway. Gene and protein characterization of OR, expression levels, protein amounts and carotenoids levels were evaluated in roots of one white (60444) and two yellow cassava cultivars (GM5309-57 and GM3736-37). Four OR variants were found in yellow cassava roots. Although comparable expression was found for three variants, significantly higher OR protein amounts were observed in the yellow varieties. In contrast, cassava PSY1 expression was significantly higher in the yellow cultivars, but PSY protein amount did not vary. Furthermore, we evaluated whether expression of one of the variants, MeOR_X1, affected carotenoid accumulation in cassava Friable Embryogenic Callus (FEC). Overexpression of maize PSY1 alone resulted in carotenoids accumulation and induced crystal formation. Co-expression with MeOR_X1 led to greatly increase of carotenoids although PSY1 expression was high in the co-expressed FEC. Our data suggest that posttranslational mechanisms controlling OR and PSY protein stability contribute to higher carotenoid levels in yellow cassava. Moreover, we showed that cassava FEC can be used to study the efficiency of single and combinatorial gene expression in increasing the carotenoid content prior to its application for the generation of biofortified cassava with enhanced carotenoids levels.

Alfa-fetoproteína y gamma-glutamiltranspeptidasa en pacientes con cirrosis hepática y carcinoma hepatocelular / Alpha-fetoprotein and gamma-glutamyltransferase in patients with liver cirrhosis and hepatocellular carcinoma

Introducción: El carcinoma hepatocelular (CHC) es una complicación de la cirrosis hepática (CH). El objetivo principal del estudio fue describir los niveles de los marcadores serológicos alfa-fetoproteína (AFP) y gamma-glutamiltranspeptidasa (GGT) en pacientes con CH y/o CHC. Métodos: Estudio de corte transversal con 99 pacientes con diagnóstico de CH y/o CHC. Resultados: Un total de 66 (66,7%) pacientes presentaban un diagnóstico de CH, 23 (23,2%) CHC asociado a CH y 10 (10,1%) CHC aislado. Los valores de AFP fueron mayores en individuos con CHC asociado a CH comparados con aquellos que solo tenían CH (20 y 2,93 ng/mL, p<0.05); los niveles de la GGT fueron también mayores en pacientes con CHC asociado a CH (208 y 109 UI/L, p<0,05). Ningún paciente con CHC tuvo en forma simultánea valores normales de AFP y GGT. Conclusiones: En pacientes con CHC asociado a CH los niveles de AFP y GGT son significativamente más altos que individuos con CH aislada.

Introduction: Hepatocellular carcinoma (HCC) is one of the complications associated with liver cirrhosis (LC). The main objective of the present study was to describe the levels of the serological markers alpha-fetoprotein (AFP) and gamma-glutamyltranspeptidase (GGT) in patients with LC and/or HCC. Methods: Cross sectional study that included 99 patients with a diagnosis of LC and/or HCC. Results: 66 (66.7%) patients had a diagnosis of LC, 23 (23.2%) had LC alongside with HCC and 10 (10.1%) had HCC without LC. AFP levels were higher in individuals with HCC associated with LC when compared with those with LC only (20 and 2.93 ng/mL, p <0.05), the levels of GGT were also higher in patients with HCC associated with LC (208 and 109 IU/L, p <0.05). Not a single patient with HCC had normal levels of AFP and GGT simultaneously. Conclusions: In patients with HCC associated with LC levels of AFP and GGT were significantly higher than those found in individuals with LC only.