Mixed effects approach to the analysis of the stepped wedge cluster randomised trial—Investigating the confounding effect of time through simulation

<div><p>Background</p><p>A stepped wedge cluster randomised trial (SWCRT) is a multicentred study which allows an intervention to be rolled out at sites in a random order. Once the intervention is initiated at a site, all participants within that site remain exposed to the intervention for the remainder of the study.</p><p>The time since the start of the study (“calendar time”) may affect outcome measures through underlying time trends or periodicity. The time since the intervention was introduced to a site (“exposure time”) may also affect outcomes cumulatively for successful interventions, possibly in addition to a step change when the intervention began.</p><p>Methods</p><p>Motivated by a SWCRT of self-monitoring for bipolar disorder, we conducted a simulation study to compare model formulations to analyse data from a SWCRT under 36 different scenarios in which time was related to the outcome (improvement in mood score). The aim was to find a model specification that would produce reliable estimates of intervention effects under different scenarios. Nine different formulations of a linear mixed effects model were fitted to these datasets. These models varied in the specification of calendar and exposure times.</p><p>Results</p><p>Modelling the effects of the intervention was best accomplished by including terms for both calendar time and exposure time. Treating time as categorical (a separate parameter for each measurement time-step) achieved the best coverage probabilities and low bias, but at a cost of wider confidence intervals compared to simpler models for those scenarios which were sufficiently modelled by fewer parameters. Treating time as continuous and including a quadratic time term performed similarly well, with slightly larger variations in coverage probability, but narrower confidence intervals and in some cases lower bias. The impact of misspecifying the covariance structure was comparatively small.</p><p>Conclusions</p><p>We recommend that unless there is a priori information to indicate the form of the relationship between time and outcomes, data from SWCRTs should be analysed with a linear mixed effects model that includes separate categorical terms for calendar time and exposure time. Prespecified sensitivity analyses should consider the different formulations of these time effects in the model, to assess their impact on estimates of intervention effects.</p></div

Antibody persistence and booster responses to split-virion H5N1 avian influenza vaccine in young and elderly adults

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 mu g of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 mu g alum-adjuvanted vaccine or 7.5 mu g dose vaccine were lower than 21days after the primary course and waned further with time. Re-immunization with the clade 2, 30 mu g alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody crossreactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available

The treatment of child anxiety disorders via guided parent-delivered cognitive-behavioural therapy: a randomised controlled trial

Background Promising evidence has emerged of clinical gains using guided self-help cognitive-behavioural therapy (CBT) for child anxiety and by involving parents in treatment; however, the efficacy of guided parent-delivered CBT has not been systematically evaluated in UK primary and secondary settings. Aims To evaluate the efficacy of low-intensity guided parent-delivered CBT treatments for children with anxiety disorders. Method A total of 194 children presenting with a current anxiety disorder, whose primary carer did not meet criteria for a current anxiety disorder, were randomly allocated to full guided parent-delivered CBT (four face-to-face and four telephone sessions) or brief guided parent-delivered CBT (two face-to-face and two telephone sessions), or a wait-list control group (trial registration: ISRCTN92977593). Presence and severity of child primary anxiety disorder (Anxiety Disorders Interview Schedule for DSM-IV, child/parent versions), improvement in child presentation of anxiety (Clinical Global Impression-Improvement scale), and change in child anxiety symptoms (Spence Children’s Anxiety Scale, child/parent version and Child Anxiety Impact scale, parent version) were assessed at post-treatment and for those in the two active treatment groups, 6 months post-treatment. Results Full guided parent-delivered CBT produced superior diagnostic outcomes compared with wait-list at post-treatment, whereas brief guided parent-delivered CBT did not: at post-treatment, 25 (50%) of those in the full guided CBT group had recovered from their primary diagnosis, compared with 16 (25%) of those on the wait-list (relative risk (RR) 1.85, 95% CI 1.14-2.99); and in the brief guided CBT group, 18 participants (39%) had recovered from their primary diagnosis post-treatment (RR = 1.56, 95% CI 0.89-2.74). Level of therapist training and experience was unrelated to child outcome. Conclusions Full guided parent-delivered CBT is an effective and inexpensive first-lin

Community treatment orders for patients with psychosis (OCTET): a randomised controlled trial

The trial is funded by a Programme Grant for Applied Research from the National Institute of Health Research (RP-PG-0606–1006

Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: an individual participant data meta-analysis

Background: Babies born preterm are at an increased risk of dying in the first weeks of life, and those who survive have a higher rate of cerebral palsy (CP) compared with babies born at term. The aim of this individual participant data (IPD) meta-analysis (MA) was to assess the effects of antenatal magnesium sulphate, compared with no magnesium treatment, given to women at risk of preterm birth on important maternal and fetal outcomes, including survival free of CP, and whether effects differed by participant or treatment characteristics such as the reason the woman was at risk of preterm birth, why treatment was given, the gestational age at which magnesium sulphate treatment was received, or the dose and timing of the administration of magnesium sulphate. Methods and findings: Trials in which women considered at risk of preterm birth (<37 weeks' gestation) were randomised to magnesium sulphate or control treatment and where neurologic outcomes for the baby were reported were eligible for inclusion. The primary outcomes were infant death or CP and severe maternal outcome potentially related to treatment. Studies were identified based on the Cochrane Pregnancy and Childbirth search strategy using the terms [antenatal or prenatal] and [magnesium] and [preterm or premature or neuroprotection or 'cerebral palsy']. The date of the last search was 28 February 2017. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. For each prespecified outcome, IPD were analysed using a 1-stage approach. All 5 trials identified were included, with 5,493 women and 6,131 babies. Overall, there was no clear effect of magnesium sulphate treatment compared with no treatment on the primary infant composite outcome of death or CP (relative risk [RR] 0.94, 95% confidence interval (CI) 0.85 to 1.05, 6,131 babies, 5 trials, p = 0.07 for heterogeneity of treatment effect across trials). In the prespecified sensitivity analysis restricted to data from the 4 trials in which the intent of treatment was fetal neuroprotection, there was a significant reduction in the risk of death or CP with magnesium sulphate treatment compared with no treatment (RR 0.86, 95% CI 0.75 to 0.99, 4,448 babies, 4 trials), with no significant heterogeneity (p = 0.28). The number needed to treat (NNT) to benefit was 41 women/babies to prevent 1 baby from either dying or having CP. For the primary outcome of severe maternal outcome potentially related to magnesium sulphate treatment, no events were recorded from the 2 trials providing data. When the individual components of the composite infant outcome were assessed, no effect was seen for death overall (RR 1.03, 95% CI 0.91 to 1.17, 6,131 babies, 5 trials) or in the analysis of death using only data from trials with the intent of fetal neuroprotection (RR 0.95, 95% CI 0.80 to 1.13, 4,448 babies, 4 trials). For cerebral palsy in survivors, magnesium sulphate treatment had a strong protective effect in both the overall analysis (RR 0.68, 95% CI 0.54 to 0.87, 4,601 babies, 5 trials, NNT to benefit 46) and the neuroprotective intent analysis (RR 0.68, 95% CI 0.53 to 0.87, 3,988 babies, 4 trials, NNT to benefit 42). No statistically significant differences were seen for any of the other secondary outcomes. The treatment effect varied little by the reason the woman was at risk of preterm birth, the gestational age at which magnesium sulphate treatment was given, the total dose received, or whether maintenance therapy was used. A limitation of the study was that not all trials could provide the data required for the planned analyses so that combined with low event rates for some important clinical events, the power to find a difference was limited. Conclusions: Antenatal magnesium sulphate given prior to preterm birth for fetal neuroprotection prevents CP and reduces the combined risk of fetal/infant death or CP. Benefit is seen regardless of the reason for preterm birth, with similar effects across a range of preterm gestational ages and different treatment regimens. Widespread adoption worldwide of this relatively inexpensive, easy-to-administer treatment would lead to important global health benefits for infants born preterm.Caroline A. Crowther, Philippa F. Middleton, Merryn Voysey, Lisa Askie, Lelia Duley, Peter G. Pryde, Stéphane Marret, Lex W. Doyle, for the AMICABLE Grou

Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array.

Current diagnostic tests for typhoid fever, the disease caused by Salmonella Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 S. Typhi antigens in sera from 41 participants challenged with oral S. Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort (n = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid (n = 100) from other febrile bacteremia (n = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever

Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials

Background Whether statin therapy is as effective in women as in men is debated, especially for primary prevention. We undertook a meta-analysis of statin trials in the Cholesterol Treatment Trialists' (CTT) Collaboration database to compare the effects of statin therapy between women and men. Methods We performed meta-analyses on data from 22 trials of statin therapy versus control (n=134 537) and five trials of more-intensive versus less-intensive statin therapy (n=39 612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1·0 mmol/L reduction in LDL cholesterol and effects in men and women compared with a Cox model that adjusted for non-sex differences. For subgroup analyses, we used 99% CIs to make allowance for the multiplicity of comparisons. Findings 46 675 (27%) of 174 149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1·1 mmol/L in statin vs control trials and roughly 0·5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1·0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio [RR] 0·84, 99% CI 0·78–0·91) and men (RR 0·78, 99% CI 0·75–0·81, adjusted p value for heterogeneity by sex=0·33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p=0·11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0·91, 99% CI 0·84–0·99) and men (RR 0·90, 99% CI 0·86–0·95; adjusted heterogeneity p=0·43). Interpretation In men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events.UK Medical Research Council, British Heart Foundation, Australian National Health and Medical Research Council, European Community Biomed Program

Typhoid conjugate vaccine effectiveness in Malawi: evaluation of a test-negative design using randomised, controlled clinical trial data

Background Typhoid conjugate vaccines are being introduced in low-income and middle-income countries to prevent typhoid illness in children. Vaccine effectiveness studies assess vaccine performance after introduction. The test-negative design is a commonly used method to estimate vaccine effectiveness that has not been applied to typhoid vaccines because of concerns over blood culture insensitivity. The overall aim of the study was to evaluate the appropriateness of using a test-negative design to assess typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine (Vi-TT) effectiveness using a gold standard randomised controlled trial database. Methods Using blood culture data from a randomised controlled trial of Vi-TT in Malawi, we simulated a test-negative design to derive vaccine effectiveness estimates using three different approaches and compared these to randomised trial efficacy results. In the randomised trial, 27 882 children aged 9 months to 12 years were randomly assigned (1:1) to receive a single dose of Vi-TT or meningococcal capsular group A conjugate vaccine between Feb 21 and Sept 27, 2018, and were followed up for blood culture-confirmed typhoid fever until Sept 30, 2021. Findings For all three test-negative design approaches, vaccine effectiveness estimates (test-negative design A, 80·3% [95% CI 66·2 to 88·5] vs test-negative design B, 80·5% [66·5 to 88·6] vs test-negative design C, 80·4% [66·9 to 88·4]) were almost identical to the randomised trial results (80·4% [95% CI 66·4 to 88·5]). Receipt of Vi-TT did not affect the risk of non-typhoid fever (vaccine efficacy against non-typhoid fever –0·4% [95% CI –4·9 to 3·9] vs –1% [–5·6 to 3·3] vs –2·5% [–6·4 to 1·3] for test-negative design A, test-negative design B, and test-negative design C, respectively). Interpretation This study validates the test-negative design core assumption for typhoid vaccine effectiveness estimation and shows the accuracy and precision of the estimates compared with the randomised controlled trial. These results show that the test-negative design is suitable for assessing typhoid conjugate vaccine effectiveness in post-introduction studies using blood culture surveillance