Search

Even modest improvements in the probability of success of selecting drug targets which are ultimately approved can substantially reduce the costs of research and development. Drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. A key enabler of identifying and validating these genetically validated targets is access to association results from genome‐wide genotyping, whole‐exome sequencing, and whole‐genome sequencing studies with observable traits (often diseases) across large numbers of individuals. Today, linkage between genotype and real‐world data (RWD) provides significant opportunities to not only increase the statistical power of genome‐wide association studies by ascertaining additional cases for diseases of interest, but also to improve diversity and coverage of association studies across the disease phenome. As RWD‐genetics linked resources continue to grow in diversity of participants, breadth of data captured, length of observation, and number of participants, there is a greater need to leverage the experience of RWD experts, clinicians, and highly experienced geneticists together to understand which lessons and frameworks from general research using RWD sources are relevant to improve genetics‐driven drug discovery and development. This paper describes new challenges and opportunities for phenotypes enabled by diverse RWD sources, considerations in the use of RWD phenotypes for disease gene identification across the disease phenome, and challenges and opportunities in leveraging RWD phenotypes in target validation. The paper concludes with views on the future directions for phenotype development using RWD, and key questions requiring further research and development to advance this nascent field. [ABSTRACT FROM AUTHOR]

Invasive group B Streptococcus (GBS) remains a leading cause of illness and death among infants globally. We conducted prospective and retrospective laboratory-based surveillance of GBS-positive cultures from infants <3 months of age in 18 hospitals across China during January 1, 2015-December 31, 2017. The overall incidence of GBS was 0.31 (95% CI 0.27-0.36) cases/1,000 live births; incidence was 0-0.76 cases/1,000 live births across participating hospitals. The case-fatality rate was 2.3%. We estimated 13,604 cases of GBS and 1,142 GBS-associated deaths in infants <90 days of age annually in China. GBS isolates were most commonly serotype III (61.5%) and clonal complex 17 (40.6%). Enhanced active surveillance and implementation of preventive strategies, such as maternal GBS vaccination, warrants further investigation in China to help prevent these infections. [ABSTRACT FROM AUTHOR]

Confounding by indication is a key challenge for pharmacoepidemiologists. Although self-controlled study designs address time-invariant confounding, indications sometimes vary over time. For example, infection might act as a time-varying confounder in a study of antibiotics and uveitis, because it is time-limited and a direct cause both of receiving antibiotics and uveitis. Methods for incorporating active comparators in self-controlled studies to address such time-varying confounding by indication have only recently been developed. In this paper we formalize these methods, and provide a detailed description for how the active comparator rate ratio can be derived in a self-controlled case series (SCCS): either by explicitly comparing the regression coefficients for a drug of interest and an active comparator under certain circumstances using a simple ratio approach, or through the use of a nested regression model. The approaches are compared in two case studies, one examining the association between thiazolidinediones and fractures, and one examining the association between fluoroquinolones and uveitis using the UK Clinical Practice Research DataLink. Finally, we provide recommendations for the use of these methods, which we hope will support the design, execution and interpretation of SCCS using active comparators and thereby increase the robustness of pharmacoepidemiological studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial results may not be generalisable and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored generalisability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), and secondary outcomes. As the pre-specified criteria were met confirming trial emulation, we then explored treatment heterogeneity among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease (CKD). In the trial-eligible population (n=137,155), results for the primary outcome demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]), meeting the pre-specified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age and CKD. This suggests that ONTARGET trial findings are generalisable to trial-underrepresented subgroups., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: To estimate the incidence, case fatality ratio and serotypes associated with early-onset (EOD) and late-onset (LOD) invasive GBS disease in infants in southern mainland China., Methods: During the six-month study period, infants aged ≤ 90 days with culture-confirmed GBS disease born in the study hospitals or elsewhere, but presenting to a study hospital, were enrolled. GBS-positive cultures were genotyped, serotyped and sequence typed. The incidence rate was calculated for infants born in the study hospitals, and case fatality ratio and causative serotypes identified for all enrolled GBS cases., Results: Ten cases were enrolled: 2 EOD cases born in the study hospitals and 8 LOD cases born elsewhere. Incidence rate was 0.28 (95% confidence interval: 0.08-1.03, n = 2/7061 successfully followed-up consenting subjects); no cases resulted in fatality. In the 8 GBS isolates available for typing, 4 serotypes (Ia, Ib, III and V) and 5 multi-locus sequence types (1, 10, 12, 17 and 23) were identified., Conclusions: This is the first study specifically investigating the incidence of GBS invasive disease in infants in southern mainland China. Incidence and case fatality were low but further research is needed in larger, more diverse cohorts to estimate disease burden for the broader Chinese population.

The chronic nature of epilepsy treatment, as well as the peak in incidence in children and adolescents, makes it likely that women of childbearing age will be exposed to antiepileptic drugs (AEDs). This has led to the establishment of several pregnancy registries to monitor the safety of anticonvulsants in terms of the risk of major birth defects following in utero exposure. Many registries are now approaching their second decade of data collection. With the release of substantial information on a range of AEDs (both older and newer generation drugs), it becomes increasingly important to understand how the methodological variations between cohorts may affect the risks of major birth defects being reported. This chapter explores the key methodological elements of these registries in terms of patient enrolment, the source of exposure and outcome information, outcome definition and ascertainment and comparator groups and how these elements may influence the reported risk estimates. With multiple registries collecting and releasing substantial data on AED safety in pregnancy, the chapter also reflects on how an increasing number of "signals" around increased risk of specific birth defects is likely. Possible methods for interpreting such signals, that the registries were not originally designed to detect and interpret, are also discussed.