Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

BACKGROUND: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. METHODS: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. RESULTS: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. CONCLUSIONS: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

Handling Partially Observed Trial Data After Treatment Withdrawal: Introducing Retrieved Dropout Reference-Base Centred Multiple Imputation.

The ICH E9(R1) Addendum (International Council for Harmonization 2019) suggests treatment-policy as one of several strategies for addressing intercurrent events such as treatment withdrawal when defining an estimand. This strategy requires the monitoring of patients and collection of primary outcome data following termination of randomised treatment. However, when patients withdraw from a study early before completion this creates true missing data complicating the analysis. One possible way forward uses multiple imputation to replace the missing data based on a model for outcome on- and off-treatment prior to study withdrawal, often referred to as retrieved dropout multiple imputation. This article introduces a novel approach to parameterising this imputation model so that those parameters which may be difficult to estimate have mildly informative Bayesian priors applied during the imputation stage. A core reference-based model is combined with a retrieved dropout compliance model, using both on- and off-treatment data, to form an extended model for the purposes of imputation. This alleviates the problem of specifying a complex set of analysis rules to accommodate situations where parameters which influence the estimated value are not estimable, or are poorly estimated leading to unrealistically large standard errors in the resulting analysis. We refer to this new approach as retrieved dropout reference-base centred multiple imputation.

Comments on 'standard and reference-based conditional mean imputation': Regulators and trial statisticians be aware!

Accurate frequentist performance of a method is desirable in confirmatory clinical trials, but is not sufficient on its own to justify the use of a missing data method. Reference-based conditional mean imputation, with variance estimation justified solely by its frequentist performance, has the surprising and undesirable property that the estimated variance becomes smaller the greater the number of missing observations; as explained under jump-to-reference it effectively forces the true treatment effect to be exactly zero for patients with missing data.

Human Nephrogenesis can Persist Beyond 40 Postnatal Days in Preterm Infants.

Introduction: Human nephrogenesis is typically completed by 36 weeks gestation; however, it is impacted by preterm birth. Early studies suggested that nephrogenesis persisted for ≤40 postnatal days in preterm infants. However, the postmenstrual age (PMA) of the preterm infants who survived >40 days was uncertain. In this study, we sought to reexamine postnatal kidney development in preterm infants surviving >40 days. Methods: Human kidney samples were obtained from an institutional biobank. Samples were considered controls if survival was ≤4 days after birth with PMA of 30 to ≤36 weeks. Kidneys from preterm neonates with postnatal survival >40 days and PMA of 30 to ≤36 weeks were compared to controls. We counted glomerular generations, measured nephrogenic zone widths (NZW), and performed immunofluorescence (IF) with SIX1 and RET. We compared kidney weights and quantified the cross-sectional area of proximal (lotus tetragonolobus lectin [LTL], SL22A2), distal (SLC12A3, KCNJ10), and glomerular (nephrin) markers using IF. Results: Seven preterm infants surviving >40 days and 8 controls were analyzed. Four of 7 preterm infants had histologic and molecular evidence of nephrogenesis. Cessation of nephrogenesis in preterm infants occurred 2 weeks earlier than PMA-matched controls with attenuated expression of both SIX1 and RET. We found increased kidney weight-to-body weight ratio, increased distal tubular cross-sectional staining in the superficial nephrons, and distal tubular hypertrophy and hyperplasia in the preterm infant kidneys. Conclusion: Our study supports that nephrogenesis in preterm infants persists longer than previously thought with evidence of early nephron stress, placing importance on the neonatal environment.

Taxonomic account and phylogenetic relationships of the species of the Neotropical social wasp genus Chartergus Lepeletier, 1836 (Vespidae: Polistinae: Epiponini).

The Neotropical social wasp genus Chartergus is reviewed and comparative diagnoses, images of type material, and an updated identification key for species are presented. To investigate the phylogenetic relationships within the genus, we used a combined dataset of morphological characters, nest architecture traits, and molecular data. The results revealed the following relationships among the Chartergus species: (C. globiventris + (C. artifex + C. metanotalis)).

Phylogenomics of Tetraopes longhorn beetles unravels their evolutionary history and biogeographic origins.

Tetraopes longhorn beetles are known for their resistance to milkweed plant toxins and their coevolutionary dynamics with milkweed plants (Asclepias). This association is considered a textbook example of coevolution, in which each species of Tetraopes is specialized to feed on one or a few species of Asclepias. A major challenge to investigating coevolutionary hypotheses and conducting molecular ecology studies lies in the limited understanding of the evolutionary history and biogeographical patterns of Tetraopes. By integrating genomic, morphological, paleontological, and geographical data, we present a robust phylogeny of Tetraopes and their relatives, using three inference methods with varying subsets of data, encompassing 2-12 thousand UCE loci. We elucidate the diversification patterns of Tetraopes species across major biogeographical regions and their colonization of the American continent. Our findings suggest that the genus originated in Central America approximately 21 million years ago during the Miocene and diversified from the Mid-Miocene to the Pleistocene. These events coincided with intense geological activity in Central America. Additionally, independent colonization events in North America occurred from the Late Miocene to the early Pleistocene, potentially contributing to the early diversification of the group. Our data suggest that a common ancestor of Tetraopini migrated into North America, likely facilitated by North Atlantic land bridges, while closely related tribes diverged in Asia and Europe during the Paleocene. Establishing a robust and densely sampled phylogeny of Tetraopes beetles provides a foundation for investigating micro- and macroevolutionary phenomena, including clinal variation, coevolution, and detoxification mechanisms in this ecologically important group.

Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials.

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status. DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.

Digital endpoints in clinical trials: emerging themes from a multi-stakeholder Knowledge Exchange event.

BACKGROUND: Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people's chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person's health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem. METHODS: A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day's discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination. RESULTS: Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event. CONCLUSIONS: The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software.

Divergence time analysis of the Neotropical wasp genus Protopolybia Ducke, 1905 (Vespidae, Polistinae, Epiponini) using a Multilocus Phylogenetic Approach.

The genus Protopolybia Ducke was analyzed using a multilocus phylogenetic approach, which confirmed its monophyly. In contrast with the arrangements derived solely from morphological data, however, this analysis divides the genus into only two major clades. The study also presents divergence times for the origin and diversification of Protopolybia, which are related to possible vicariant events occurring in the Amazon biome.

Taxonomic notes on the genus Charterginus Fox, 1898 (Vespidae: Polistinae: Epiponini) with images of the type specimens and new occurrence records.

Charterginus Fox, 1898 is a neotropical genus of swarm-founding social wasps consisting of six species. Despite its ecological significance, there are limited studies on various aspects of these wasps. To address this, this study aims to provide a comprehensive comparative diagnosis for all Charterginus species, accompanied by high-quality images of the type material. Moreover, a distribution map incorporating both previous and newly recorded occurrences is presented, shedding light on the geographical range of these species. Through these efforts, we aim to enhance the knowledge and facilitate future research on Charterginus, ultimately contributing to a better understanding of swarm-founding social wasps.

Keys to the Costa Rican species of paper wasps (Hymenoptera: Vespidae: Polistinae)

Paper wasps (subfamily Polistinae) are one of the four main groups of eusocial insects in the Neotropics. They are medically important for the frequent stings inflicted on humans, but at the same time are valuable predators of pest insects. Nonetheless, there are no updated keys for the identification of the Central American species. Here we provide keys to the 18 genera and 106 species known to occur in Costa Rica, illustrated with one hundred original line drawings.

Las avispas de la subfamilia Polistinae son uno de los cuatro grupos principales de insectos eusociales en el neotrópico, y son de importancia económica tanto por sus picaduras como por su papel en control biológico. Sin embargo, no existen claves actualizadas para la identificación de las especies de América Central. Aquí se proveen claves ilustradas para los 18 géneros y las 106 especies conocidas de Costa Rica y se incluyen cien dibujos originales.

Catalog of the Neotropical Masarinae (Hymenoptera, Vespidae)

A comprehensive catalog of the Neotropical Masarinae is presented. The lectotype of Trimeria howardi Bertoni, 1911, is designated.

Um catálogo completo dos Masarinae Neotropicais é apresentado. O lectótipo de Trimeria howardi Bertoni, 1911 é designado.

Males of Nectarinella Bequaert (Hymenoptera, Vespidae, Polistinae)

Os machos das duas espécies de vespas sociais do gênero Nectarinella Bequaert, N. xavantinensis Mateus & Noll e N. championi (Dover), são descritos e suas genitálias ilustradas. São feitas comparações com espécies de gêneros estreitamente relacionados, Chartergellus, Leipomeles, Marimbonda, Parachartergus e Pseudopolybia.