Maintaining the validity of inference from linear mixed models in stepped-wedge cluster randomized trials under misspecified random-effects structures

Linear mixed models are commonly used in analyzing stepped-wedge cluster randomized trials (SW-CRTs). A key consideration for analyzing a SW-CRT is accounting for the potentially complex correlation structure, which can be achieved by specifying a random effects structure. Common random effects structures for a SW-CRT include random intercept, random cluster-by-period, and discrete-time decay. Recently, more complex structures, such as the random intervention structure, have been proposed. In practice, specifying appropriate random effects can be challenging. Robust variance estimators (RVE) may be applied to linear mixed models to provide consistent estimators of standard errors of fixed effect parameters in the presence of random-effects misspecification. However, there has been no empirical investigation of RVE for SW-CRT. In this paper, we first review five RVEs (both standard and small-sample bias-corrected RVEs) that are available for linear mixed models. We then describe a comprehensive simulation study to examine the performance of these RVEs for SW-CRTs with a continuous outcome under different data generators. For each data generator, we investigate whether the use of a RVE with either the random intercept model or the random cluster-by-period model is sufficient to provide valid statistical inference for fixed effect parameters, when these working models are subject to misspecification. Our results indicate that the random intercept and random cluster-by-period models with RVEs performed similarly. The CR3 RVE estimator, coupled with the number of clusters minus two degrees of freedom correction, consistently gave the best coverage results, but could be slightly anti-conservative when the number of clusters was below 16. We summarize the implications of our results for linear mixed model analysis of SW-CRTs in practice.Comment: Correct figure legend and table Typo

Male circumcision and Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis: observations after a randomised controlled trial for HIV prevention

International audienceOBJECTIVE: To assess the association between male circumcision and Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis using data from a male circumcision randomised controlled trial. METHODS: We used data collected during the male circumcision trial conducted in Orange Farm (South Africa) among men aged 18-24 years. Altogether, 1767 urine samples collected during the final follow-up visit were analysed using PCR. Prevalence of N gonorrhoeae, C trachomatis and T vaginalis was assessed as a function of male circumcision using odds ratios (OR) given by univariate and multivariate logistic regression. RESULTS: In an intention-to-treat analysis, prevalence of N gonorrhoeae, C trachomatis and T vaginalis among intervention and control groups were 10.0% versus 10.3% (OR 0.97; p = 0.84), 2.1% versus 3.6% (OR 0.58; p = 0.065) and 1.7% versus 3.1% (OR 0.54; p = 0.062), respectively. The association between T vaginalis and male circumcision remained borderline when controlling for age, ethnic group, number of lifetime partners, marital status, condom use and HIV status (AOR 0.48; p = 0.069). In the as-treated analysis, this association became significant (OR 0.49, p = 0.030; AOR 0.41, p = 0.030). CONCLUSIONS: This study demonstrates for the first time that male circumcision reduces T vaginalis infection among men. This finding explains why women with circumcised partners are less at risk for T vaginalis infection than other women. The protective effect on T vaginalis is an additional argument to recommend male circumcision in Africa where it is acceptable

The use of segmented regression in analysing interrupted time series studies : an example in pre-hospital ambulance care

Peer reviewedPublisher PD

Advancing ecosystem accounting in estuaries: Swartkops Estuary case study

Rapid degradation of ecosystems and loss of ecosystem services have sparked interest in developing approaches to report and integrate such change with socio-economic information systems, such as the System of National Accounts. Here we describe an approach and application of ecosystem accounting for individual estuaries, building on approaches previously applied at national and bay levels. Using the Swartkops Estuary as a case study, the focus is on physical accounts for ecosystem extent and condition, as well as accounts for two important ecosystem services (carbon sequestration and recreational use). Pressure accounts are also introduced to demonstrate the value of identifying key areas for management and restoration interventions in response to changes in extent and/or condition accounts. Greater resolution in these account reports, achieved through zoning, provides spatially explicit information on ecosystem assets and their services within an estuary to also inform management decision-making at local level. Further, these accounts can also inform local restoration prioritisation, in support of the UN Decade on Ecosystem Restoration (2021–2030), for example offsetting irreversibly degraded areas in one zone with restoration or maintenance of similar habitats in another. Significance: • This study is the first to apply the ecosystem accounting approach at the individual estuary level. • We provide spatially explicit information on ecosystem assets and their services in support of resource management. • Physical accounts include extent and condition, as well as ecosystem service and pressure accounts. • These accounts inform estuary management and restoration at the local governance level

Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials

Taljaard, M., Goldstein, C. E., Giraudeau, B., Nicholls, S. G., Carroll, K., Hey, S. P., … Weijer, C. (2020). Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials. Clinical Trials. Copyright © The Author(s), 2020. DOI: https://doi.org/10.1177/174077451989679

HIV and SARS-CoV-2 co-infection: The diagnostic challenges of dual pandemics

The first critically ill patient admitted to our hospital in Cape Town, South Africa, during the COVID-19 pandemic was co-infected with HIV and SARS-CoV-2. Pneumocystis jirovecii pneumonia (PCP) and other respiratory opportunistic infections share many clinical features with severe COVID-19. Our understanding of the nuances of co-management of HIV and COVID-19 is evolving. We describe the diagnostic and therapeutic challenges presented by this case

Urgently seeking efficiency and sustainability of clinical trials in global health

This paper shows the scale of global health research and the context in which we frame the subsequent papers in the Series. In this Series paper, we provide a historical perspective on clinical trial research by revisiting the 1948 streptomycin trial for pulmonary tuberculosis, which was the first documented randomised clinical trial in the English language, and we discuss its close connection with global health. We describe the current state of clinical trial research globally by providing an overview of clinical trials that have been registered in the WHO International Clinical Trial Registry since 2010. We discuss challenges with current trial planning and designs that are often used in clinical trial research undertaken in low-income and middle-income countries, as an overview of the global health trials landscape. Finally, we discuss the importance of collaborative work in global health research towards generating sustainable and culturally appropriate research environments