Understanding between-cluster variation in prevalence, and limits for how much variation is plausible

In clinical trials and observational studies of clustered binary data, understanding between-cluster variation is essential: in sample size and power calculations of cluster randomised trials, for example, the intra-cluster correlation coefficient is often specified. However, quantifications of between-cluster variation can be unintuitive, and an intra-cluster correlation coefficient as low as 0.04 may correspond to surprisingly large between-cluster differences. We suggest that understanding is improved through visualising the implied distribution of true cluster prevalences – possibly by assuming they follow a beta distribution – or by calculating their standard deviation, which is more readily interpretable than the intra-cluster correlation coefficient. Even so, the bounded nature of binary data complicates the interpretation of variances as primary measures of uncertainty, and entropy offers an attractive alternative. Appealing to maximum entropy theory, we propose the following rule of thumb: that plausible intra-cluster correlation coefficients and standard deviations of true cluster prevalences are both bounded above by the overall prevalence, its complement, and one third. We also provide corresponding bounds for the coefficient of variation, and for a different standard deviation and intra-cluster correlation defined on the log odds scale. Using previously published data, we observe the quantities defined on the log odds scale to be more transportable between studies with different outcomes with different prevalences than the intra-cluster correlation and coefficient of variation. The latter increase and decrease, respectively, as prevalence increases from 0% to 50%, and the same is true for our bounds. Our work will help clinical trialists better understand between-cluster variation and avoid specifying implausibly high values for the intra-cluster correlation in sample size and power calculations

Spatial patterns of scour and fill in dryland sand bed streams

Reproduced with permission of the publisher. © 2006 American Geophysical UnionSpatial patterns of scour and fill in two dryland ephemeral stream channels with sandy bed material have been measured with dense arrays of scour chains. Although the depth and areal extent of bed activity increased with discharge, active bed reworking at particular locations within the reaches resulted in downstream patterns of alternate shallower and deeper areas of scour. The variation was such that mean scour depths for individual cross sections varied about the mean for the reach by a factor of 2–4 while the locus of maximum scour traced a sinuous path about the channel centerline. The wavelength of the pattern of scour was about seven times the channel width. During each event, compensating fill returned the streambeds to preflow elevations, indicating that the streams were in approximate steady state over the period of study. Although the patterns of periodically enhanced scour along alternate sides of the channels are consistent with models of periodically reversing helical flow, further work is required to identify the causal relationships between patterns of flow and sediment transport in dryland sand bed channels

PneuMum: Impact from a randomised controlled trial of maternal 23-valent pneumococcal polysaccharide vaccination on middle ear disease amongst Indigenous infants, Northern Territory, Australia

BackgroundWe assessed maternal 23-valent pneumococcal polysaccharide (23vPPV) vaccine efficacy (VE) against middle ear disease and pneumococcal carriage amongst Australian Indigenous infants.MethodsIn an open label, allocation concealed, outcome-assessor blinded, community stratified, randomised controlled trial, healthy pregnant Indigenous women aged 17–39 years in the Northern Territory of Australia received the 23vPPV (1:1:1) at: 30–36 weeks gestation, birth, or were unvaccinated (ClinicalTrials.gov NCT00714064). Co-primary outcomes were the point prevalences of infant middle ear disease and 23vPPV-type carriage at age 7 months.ResultsThe consent rate was 50% (313/632). Among 227 eligible participants randomised, retention rates were 86% (66/77) controls; 89% (67/75) pregnancy vaccinees; 88% (66/75) birth vaccinees. At infant age 7 months, ear disease prevalence was: 71% (47/66) controls, 63% (42/67) pregnancy vaccinees, 76% (50/66) birth vaccinees; and 23vPPV-type carriage was: 26% (17/66) controls, 18% (12/67) pregnancy vaccinees, 18% (12/66) birth vaccinees. For pregnancy vaccinees, VE was 12% (95% CI −12% to 31%) against infant ear disease and 30% (95% CI −34% to 64%) against 23vPPV-type carriage. In a post-hoc analysis, VE against infant ear disease concurrent with carriage of 23vPPV or related types was 51% (95% CI −2% to 76%). There were no serious adverse effects following receipt of the 23vPPV in pregnancy or at birth.ConclusionsIn a high risk population, our study was unable to demonstrate efficacy of 23vPPV in pregnancy against the co-primary outcomes of either all-cause infant ear disease or 23vPPV-type nasopharyngeal carriage at age 7 months. Efficacy against ear disease concurrent with carriage of vaccine-related serotypes (a more specific outcome) suggests 23vPPV in pregnancy may complement childhood pneumococcal vaccination programs

Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease

The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the , or genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 subjects with non-HFE HH was extracted from 53 publications and compared with data from 984 subjects with -p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in subjects with HFE HH

miRNA-Seq identifies a serum miRNA panel, which combined with APRI can detect and monitor liver disease in paediatric Cystic Fibrosis

Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on non-specific assessments, while liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical and imaging assessments as follows: CFLD (n=44), CF patients with no evidence of liver disease (CFnoLD, n=40) and healthy controls (n=40). Serum miRNAs were analysed using miRNA-sequencing. Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, while miR-142-3p and let-7g-5p were downregulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an AUROC=0.91 (sensitivity=83%, specificity=92%;

Reduced red blood cell deformability in Plasmodium knowlesi malaria

The simian parasite Plasmodium knowlesi can cause severe and fatal human malaria. However, little is known about the pathogenesis of this disease. In falciparum malaria, reduced red blood cell deformability (RBC-D) contributes to microvascular obstruction and impaired organ perfusion. In P knowlesi infection, impaired microcirculatory flow has been observed in Macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. However, RBC-D has not been measured in human infection or in the natural host M fascicularis (long-tailed macaques). Using ektacytometry, we measured RBC-D in adults with severe and non-severe knowlesi and falciparum malaria and in healthy controls. In addition, we used micropipette aspiration to determine the relative stiffness of infected RBCs (iRBCs) and uninfected RBCs (uRBCs) in P knowlesi-infected humans and M fascicularis. Ektacytometry demonstrated that RBC-D overall was reduced in human knowlesi malaria in proportion to disease severity, and in severe knowlesi malaria, it was comparable to that of severe falciparum malaria. RBC-D correlated inversely with parasitemia and lactate in knowlesi malaria and HRP2 in falciparum malaria, and it correlated with hemoglobin nadir in knowlesi malaria. Micropipette aspiration confirmed that in humans, P knowlesi infection increased stiffness of both iRBCs and uRBCs, with the latter mostly the result of echinocytosis. In contrast, in the natural host M fascicularis, echinocyte formation was not observed, and the RBC-D of uRBCs was unaffected. In unnatural primate hosts of P knowlesi, including humans, reduced deformability of iRBCs and uRBCs may represent a key pathogenic mechanism leading to microvascular accumulation, impaired organ perfusion, and anemia

Otitis media outcomes of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine and 13-valent pneumococcal conjugate vaccine schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial.

BACKGROUND: Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months. METHODS: In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2-4-6 months (_PPP), Synflorix™ (S) at 2-4-6 months (_SSS), or Synflorix™ at 1-2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM). RESULTS: Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM. CONCLUSIONS: Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life. TRIAL REGISTRATION: ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.gov NCT01174849 registered 04/08/2010

Effect of a price discount and consumer education strategy on food and beverage purchases in remote Indigenous Australia: a stepped-wedge randomised controlled trial

Background Evidence is mounting that price discounts can be effective in improving diet. This study examined the effectiveness of a 20% price discount on food and drink purchases with and without consumer education in remote Indigenous Australia. Methods A 20% discount on fruit, vegetables, water, and artificially sweetened soft drinks was applied for 24 weeks in 20 communities in remote Indigenous Australia where the community store was managed by the Arnhem Land Progress Aboriginal Corporation (ALPA) or Outback Stores (OBS) in a stepped-wedge randomised trial. Communities were randomly allocated to a fixed framework of five sets of four stratified by store association; ten stores (two in each set) were randomly assigned to receive consumer education. A store from each of the ALPA and OBS store groups (contained in separate opaque envelopes) was selected, and stores in turn continued to be consecutively allocated to the fixed store set framework, starting with the first store slot in the first store set, until all stores had been allocated. The effect of the discount on the weight of fruit and vegetables purchased (the primary endpoint) was assessed using weekly store sales data and mixed models per protocol. We did sensitivity analyses by repeating the analyses with the outliers included and repeating the analyses for the primary outcome measure removing each store one at a time. This trial was registered with Australian New Zealand Clinical Trials Registry, number ACTRN12613000694718. Findings Weekly store sales data on all food and drink products sold in 20 stores were collected from July 1, 2012, to Dec 28, 2014. Price discount alone was associated with a 12&middot;7% (95% CI 4&middot;1&ndash;22&middot;1) increase in purchases in grams of fruit and vegetables combined (primary outcome), and a 19&middot;8% (6&middot;2&ndash;35&middot;1) increase post discount (after vs before); an effect of 12 g and 18 g per capita per day. Sensitivity analyses did not modify the results for the primary outcome measure. Interpretation A 20% discount can only increase fruit and vegetable purchases to help protect against obesity and diet related disease to a certain extent. Large discounts might have a greater impact than small discounts. Creative merchandising approaches to consumer education could also be considered alongside fiscal interventions to achieve marked improvements in diet.<br /