Clinical phenotypes and outcomes in children with multisystem inflammatory syndrome across SARS-CoV-2 variant eras: a multinational study from the 4CE consortium.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras. Methods: We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using Alpha as reference. Meta-analysis was used to pool data across sites. Findings: Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the Alpha era, 111 (19%) in the Delta era, and 104 (17%) in the Omicron era. Compared with patients admitted in the Alpha era, those admitted in the Delta era were younger (ES -1.18 years [95% CI -2.05, -0.32]), had fewer respiratory symptoms (RD -0.15 [95% CI -0.33, -0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD -0.35 [95% CI -0.64, -0.07]), lower lymphocyte count (ES -0.16 × 109/uL [95% CI -0.30, -0.01]), lower C-reactive protein (ES -28.5 mg/L [95% CI -46.3, -10.7]), and lower troponin (ES -0.14 ng/mL [95% CI -0.26, -0.03]). Patients admitted in the Omicron versus Alpha eras were younger (ES -1.6 years [95% CI -2.5, -0.8]), had less frequent SIRS (RD -0.18 [95% CI -0.30, -0.05]), lower lymphocyte count (ES -0.39 × 109/uL [95% CI -0.52, -0.25]), lower troponin (ES -0.16 ng/mL [95% CI -0.30, -0.01]) and less frequently received anticoagulation therapy (RD -0.19 [95% CI -0.37, -0.04]). Length of hospitalization was shorter in the Delta versus Alpha eras (-1.3 days [95% CI -2.3, -0.4]). Interpretation: Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in Delta and Omicron eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time. Funding: None.

Estimating the Efficiency Gain of Covariate-Adjusted Analyses in Future Clinical Trials Using External Data.

We present a framework for using existing external data to identify and estimate the relative efficiency of a covariate-adjusted estimator compared to an unadjusted estimator in a future randomized trial. Under conditions, these relative efficiencies approximate the ratio of sample sizes needed to achieve a desired power. We develop semiparametrically efficient estimators of the relative efficiencies for several treatment effect estimands of interest with either fully or partially observed outcomes, allowing for the application of flexible statistical learning tools to estimate the nuisance functions. We propose an analytic Wald-type confidence interval and a double bootstrap scheme for statistical inference. We demonstrate the performance of the proposed methods through simulation studies and apply these methods to estimate the efficiency gain of covariate adjustment in Covid-19 therapeutic trials.

Seasonal Variation in the Diagnosis of Retinoblastoma.

PURPOSE: To determine the seasonal variation in the diagnosis of retinoblastoma in a global sample of children and to investigate predictors of seasonal trends. METHODS: Data were collected through a global, multicenter, 1-year cross-sectional analysis that included all treatment- naïve retinoblastoma patients presenting to participating centers between January 1, 2017, and December 31, 2017. Due to variations in days per month, data were normalized to a 30-day/month calendar. Observed data were compared to a simulation study of expected results using a uniform distribution. RESULTS: Patient-level data were available for 4,351 children from 276 centers in 153 countries, of which 3,966 had a month of presentation recorded. There were relative peaks in disease presentation in January and July, with lower counts in November and December (p = .0015). No covariates were found to be significantly associated with the seasonal trend. Two covariates, patient age at presentation and extraocular tumor spread, showed a moderate association with month of presentation. CONCLUSION: Our findings suggest seasonal trends in the presentation of retinoblastoma across the world. However, these trends do not appear to be related to income level of a country, climate, or other covariates. Any connection between seasonal variation of retinoblastoma presentation and retinoblastoma outcomes remains unclear or not present.

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country.

Paired serial limiting dilution assays.

Serial limiting dilution (SLD) assays are a widely used tool in many areas of public health research to measure the concentration of target entities. This concentration can be estimated via maximum likelihood. Asymptotic as well as exact inference methods have been proposed for hypothesis testing and confidence interval construction in this one-sample problem. However, in many scientific applications, it may be of interest to compare the concentration of target entities between a pair of samples and construct valid confidence intervals for the difference in concentrations. In this paper, an exact, computationally efficient inferential procedure is proposed for hypothesis testing and confidence interval construction in the two-sample SLD assay problem. The proposed exact method is compared to an approach based on asymptotic approximations in simulation studies. The methods are illustrated using data from the University of North Carolina HIV Cure Center.

Estimating the Efficiency Gain of Covariate-Adjusted Analyses in Future Clinical Trials Using External Data.

We present a general framework for using existing data to estimate the efficiency gain from using a covariate-adjusted estimator of a marginal treatment effect in a future randomized trial. We describe conditions under which it is possible to define a mapping from the distribution that generated the existing external data to the relative efficiency of a covariate-adjusted estimator compared to an unadjusted estimator. Under conditions, these relative efficiencies approximate the ratio of sample size needed to achieve a desired power. We consider two situations where the outcome is either fully or partially observed and several treatment effect estimands that are of particular interest in most trials. For each such estimand, we develop a semiparametrically efficient estimator of the relative efficiency that allows for the application of flexible statistical learning tools to estimate the nuisance functions and an analytic form of a corresponding Wald-type confidence interval. We also propose a double bootstrap scheme for constructing confidence intervals. We demonstrate the performance of the proposed methods through simulation studies and apply these methods to data to estimate the relative efficiency of using covariate adjustment in Covid-19 therapeutic trials.

The Convex Mixture Distribution: Granger Causality for Categorical Time Series.

We present a framework for learning Granger causality networks for multivariate categorical time series based on the mixture transition distribution (MTD) model. Traditionally, MTD is plagued by a nonconvex objective, non-identifiability, and presence of local optima. To circumvent these problems, we recast inference in the MTD as a convex problem. The new formulation facilitates the application of MTD to high-dimensional multivariate time series. As a baseline, we also formulate a multi-output logistic autoregressive model (mLTD), which while a straightforward extension of autoregressive Bernoulli generalized linear models, has not been previously applied to the analysis of multivariate categorial time series. We establish identifiability conditions of the MTD model and compare them to those for mLTD. We further devise novel and efficient optimization algorithms for MTD based on our proposed convex formulation, and compare the MTD and mLTD in both simulated and real data experiments. Finally, we establish consistency of the convex MTD in high dimensions. Our approach simultaneously provides a comparison of methods for network inference in categorical time series and opens the door to modern, regularized inference with the MTD model.

[Effects of different landscape patch structure on the diversity of arthropod community in tea plantations].

A field survey with random block design was conducted to study the effects of different landscape patch structure on the arthropod community in tea plantations. In the tea plantations with small woodland (QM) or Acacia confuse (XS) patches, predatory spider had the highest proportion, occupying 62.3% and 69.5% of the total arthropods, respectively, being significantly higher than that in the tea plantations close to paddy field (DT) or near a village (RJ). The tea plantations with QM had the highest diversity index and species richness of arthropod community, while the evenness index and dominance index were not significantly different from the other tea plantations. The tea plantations with QM and XS had much richer natural enemies, and the order of the diversity index, evenness index, and richness index of natural enemies in the tea plantations ranked as QM > XS > DT > RJ. It was suggested that landscape patch structure had great effect on the diversity of arthropod community in tea plantations.

[Determination of four polycyclic aromatic hydrocarbons in anthracene oil for toys by high performance liquid chromatography with diode array detection and fluorescence detection].

A method using high performance liquid chromatography with diode array detection coupled with fluorescence detection was applied to determine four polycyclic aromatic hydro carbons in anthracene oil for toys. This method showed good abilities of the baseline separation and high sensitivity under the optimized analytical conditions. The limits of the fluorescence detection were 0.5 - 1000 microg/L, while the limits of the diode array detection were 0.5 - 1 000 mg/L. The precisions of the method were 0.7% - 8.8%. The recoveries of the standard samples were 70.0% - 120%. The limits of detection (LOD) of anthracene, pyrene, phenanthrene and fluoranthene were 0.1, 0.1, 0.2 and 0.3 microg/L, and the limits of quantitation (LOQ) of the four substances were 0.4, 0.2, 0.5 and 0.8 microg/L, respectively. In comparison with other methods, the method has higher detection speed and lower detection limits, which is useful to analyze rapidly those four polycyclic aromatic hydrocarbons in anthracene oil for toys.