Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons ...for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect.
To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and
using bi-directional two-sample Mendelian randomization (MR) analysis.
We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (
= 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10
). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods.
In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD;
= 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD;
= 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis.
Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis.
Missing data are an inevitable challenge in Randomised Controlled Trials (RCTs), particularly those with Patient Reported Outcome Measures. Methodological guidance suggests that to avoid incorrect ...conclusions, studies should undertake sensitivity analyses which recognise that data may be 'missing not at random' (MNAR). A recommended approach is to elicit expert opinion about the likely outcome differences for those with missing versus observed data. However, few published trials plan and undertake these elicitation exercises, and so lack the external information required for these sensitivity analyses. The aim of this paper is to provide a framework that anticipates and allows for MNAR data in the design and analysis of clinical trials.
We developed a framework for performing and using expert elicitation to frame sensitivity analysis in RCTs with missing outcome data. The framework includes the following steps: first defining the scope of the elicitation exercise, second developing the elicitation tool, third eliciting expert opinion about the missing outcomes, fourth evaluating the elicitation results, and fifth analysing the trial data. We provide guidance on key practical challenges that arise when adopting this approach in trials: the criteria for identifying relevant experts, the outcome scale for presenting data to experts, the appropriate representation of expert opinion, and the evaluation of the elicitation results.The framework was developed within the POPPI trial, which investigated whether a preventive, complex psychological intervention, commenced early in ICU, would reduce the development of patient-reported post-traumatic stress disorder symptom severity, and improve health-related quality of life. We illustrate the key aspects of the proposed framework using the POPPI trial.
For the POPPI trial, 113 experts were identified with potentially suitable knowledge and asked to participate in the elicitation exercise. The 113 experts provided 59 usable elicitation questionnaires. The sensitivity analysis found that the results from the primary analysis were robust to alternative MNAR mechanisms.
Future studies can adopt this framework to embed expert elicitation within the design of clinical trials. This will provide the information required for MNAR sensitivity analyses that examine the robustness of the trial conclusions to alternative, but realistic assumptions about the missing data.
Abstract
Background
The FIRST-ABC trial comprises of two pragmatic, multicentre, parallel groups, non-inferiority randomised clinical trials designed to evaluate the clinical non-inferiority of ...first-line use of high flow nasal cannula (HFNC) to continuous positive airway pressure (CPAP) in critically ill children who require non-invasive respiratory support (NRS).
Objectives
To describe the pre-specified statistical and health economic analysis for the FIRST-ABC trial before completion of patient recruitment and data collection.
Methods
The statistical analysis plan was designed by the chief investigators and statisticians. We define the primary and secondary outcomes, summarise methods for data collection and safety monitoring, and present a detailed description of the planned statistical and health economic analysis.
Results
The primary clinical outcome is time to liberation from respiratory support. The primary effect estimate will be the adjusted hazard ratio, reported with a 95% confidence interval. As a sensitivity analysis, the primary analysis will be repeated using time to start weaning of NRS. Subgroup analyses will be performed to test for interactions between the effect of allocated treatment group and pre-specified baseline covariates. The health economic analysis will follow the intention-to-treat principle and report the mean (95% confidence interval) incremental costs, quality-adjusted life years (QALYs) and cost-effectiveness up to 6 months. All analyses will be performed separately for each of the two trials, and any results will not be combined.
Conclusion
The FIRST-ABC trial will assess the non-inferiority of HFNC compared to CPAP in two parallel trials with shared infrastructure (step-up RCT and step-down RCT). We have developed a pre-specified statistical and health economics analysis plan for the FIRST-ABC study before trial completion to minimise analytical bias.
Trial registration
ISRCTN
ISRCTN60048867
. Registered on 19 June 2019.
Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.
To ...determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure MAP target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.
A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.
Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).
The primary clinical outcome was all-cause mortality at 90 days.
Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean SD age 75 years 7 years; 1387 57% men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 3.2% vs 33 2.5%) and supraventricular cardiac arrhythmia (12 0.9% vs 13 1.0%).
Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.
isrctn.org Identifier: ISRCTN10580502.
Over 80% of psychosis patients experience cognitive impairment. Heritability of both psychosis and cognition means cognitive performance could be an endophenotype for psychosis.
In a sample with ...4,827 adults and 5,742 children, we investigated the effect of polygenic risk scores (PRSs) for schizophrenia and bipolar disorder on cognitive performance. We also assessed whether intelligence and educational attainment PRSs could predict psychosis presentation.
Schizophrenia PRS was negatively associated with visuospatial processing/problem-solving in the adult sample (β: -0.0770; 95% confidence interval CI: -0.114, -0.0403) and working memory (β: -0.171; 95% CI: -0.264, -0.0774), processing speed (β: -0.158; 95% CI: -0.250, -0.0658), episodic memory (βs: -0.178 to -0.187; 95% CIs: -0.284 to -0.0807), language (β: -0.171; 95% CI: -0.263, -0.0802), fluid intelligence (β: -0.194; 95% CI: -0.286, -0.101), and total intelligence (β: -0.186; 95% CI: -0.275, -0.0969) in the child sample. Bipolar disorder PRS was not associated with cognitive endophenotypes after Bonferroni correction. Lower intelligence PRS identified psychosis cases from controls in adults (odds ratio OR: 0.884; 95% CI: 0.809–0.966) and those experiencing prodromal psychosis symptoms in childhood (OR: 0.786; 95% CI: 0.725–0.852). Lower educational attainment PRS was associated with prodromal symptoms (OR: 0.713; 95% CI: 0.658–0.773).
The relationship between psychosis and cognitive impairment can be demonstrated bidirectionally at the neurobiological level. The effect of schizophrenia PRS and bipolar disorder PRS on cognitive performance differ from each other and across cognitive domains. These specific domains may therefore be better endophenotypes than general cognition.
Purpose
To describe critical care patients with COVID-19 across England, Wales and Northern Ireland and compare them with a historic cohort of patients with other viral pneumonias (non-COVID-19) and ...with international cohorts of COVID-19.
Methods
Extracted data on patient characteristics, acute illness severity, organ support and outcomes from the Case Mix Programme, the national clinical audit for adult critical care, for a prospective cohort of patients with COVID-19 (February to August 2020) are compared with a recent retrospective cohort of patients with other viral pneumonias (non-COVID-19) (2017–2019) and with other international cohorts of critical care patients with COVID-19, the latter identified from published reports.
Results
10,834 patients with COVID-19 (70.1% male, median age 60 years, 32.6% non-white ethnicity, 39.4% obese, 8.2% at least one serious comorbidity) were admitted across 289 critical care units. Of these, 36.9% had a PaO
2
/FiO
2
ratio of ≤ 13.3 kPa (≤ 100 mmHg) consistent with severe ARDS and 72% received invasive ventilation. Acute hospital mortality was 42%, higher than for 5782 critical care patients with other viral pneumonias (non-COVID-19) (24.7%), and most COVID-19 deaths (88.7%) occurred before 30 days. Meaningful international comparisons were limited due to lack of standardised reporting.
Conclusion
Critical care patients with COVID-19 were disproportionately non-white, from more deprived areas and more likely to be male and obese. Conventional severity scoring appeared not to adequately reflect their acute severity, with the distribution across PaO
2
/FiO
2
ratio categories indicating acutely severe respiratory disease. Critical care patients with COVID-19 experience high mortality and place a great burden on critical care services.
The co-occurrence of stroke and psychosis is a serious neuropsychiatric condition but little is known about the course of this comorbidity. We aimed to estimate longitudinal associations between ...stroke and psychosis over 10 years.
A 10-year population-based study using data from the English Longitudinal Study of Ageing. A structured health assessment recorded (i) first-occurrence stroke and (ii) psychosis, at each wave. Each were considered exposures and outcomes in separate analyses. Logistic and Cox proportional hazards regression and Kaplan-Meier methods were used. Models were adjusted for demographic and health behaviour covariates, with missing covariates imputed using random forest multiple imputation.
Of 19 808 participants, 24 reported both stroke and psychosis (median Wave 1 age 63, 71% female, 50% lowest quintile of net financial wealth) at any point during follow-up. By 10 years, the probability of an incident first stroke in participants with psychosis was 21.4% 95% confidence interval (CI) 12.1-29.6 compared to 8.3% (95% CI 7.8-8.8) in those without psychosis (absolute difference: 13.1%; 95% CI 20.8-4.3, log rank
< 0.001; fully-adjusted hazard ratio (HR): 3.57; 95% CI 2.18-5.84). The probability of reporting incident psychosis in participants with stroke was 2.3% (95% CI 1.4-3.2) compared to 0.9% (95% CI 0.7-1.1) in those without (absolute difference: 1.4%; 95% CI 0.7-2.1, log rank
< 0.001; fully-adjusted HR: 4.98; 95% CI 2.55-9.72).
Stroke is an independent predictor of psychosis (and vice versa), after adjustment for potential confounders.
As the breadth of pharmacogenetic (PGx) technologies used for research and clinical testing has been developing, so has the question of which methodology is most appropriate for every application. ...Based on the aim of the Using Genetics to Personalise Antipsychotic Treatment (G-PAT) study to accurately characterize the pharmacogenetic profile of key genes involved in antipsychotic treatment response, we have performed different genotyping assays to try and capture the entire genetic diversity of our study cohort. By furthering our understanding of the strengths and the limitations of each methodology, we aim to develop a holistic and cost-effective approach to the characterization of key pharmacogenes.
Prospective study comparing treatment as usual with antipsychotic medications versus treatment with antipsychotics informed by pharmacogenetics testing. Participants: people with psychosis taking an antipsychotic recruited across England (UK) by self-referral or from 11 National Health Service centres. Patients donated a saliva or blood sample for DNA extraction and biobanking at University College London. We tested a multi-gene panel selected from evidence-based pharmacogenetic clinical guidelines for antipsychotics or antidepressants (CYP2D6, CYP1A2, CYP3A4, CYP2C19, CYP2B6, other). We conducted further testing on whole genome genotyping arrays. We measured turnaround times, variant coverage, and costs of different technologies. Ongoing research is aimed at validating a subset of rare variants using long-read sequencing and novel variant-calling software.
We tested ∼960 variants from 220 adults with psychosis. Average age 42 years, SD 15, range 18-91 years. Sex: 48% female. Ancestry: 12% identified as Asian/Asian-British, 11% as Black/Black-British/Caribbean/African, 68% White/European and 9% reported multiple/other ancestries. Genotyping was performed with three different technologies (a PCR panel, a multi-gene panel and genome-wide genotyping array with enhanced PGx). We focused on the differences in coverage between the methods regarding CYP2D6, as it is known to be difficult to characterize. The star allele coverage between the two methods varied considerably, with the panel covering 23 alleles, whereas the genotyping arrays covered 135 alleles. This coverage difference was also observed for other relevant pharmacogenes, including CYP2C19. Independent testing with PCR methods provided very consistent results with the multi-gene panel approach including copy number variants on the CYP2D6 gene.
These findings are in-line with the technological concepts behind these two methods. Array-based genotyping methods generally cover exponentially more targets than multi-gene panels do, due to their development for use in GWAS studies, with some of the alleles covered by the array methods being present at a very low frequency in the population. The main benefit of multi-gene panels, especially for a targeted clinical service use, is that they incorporate strategies for pseudogene disambiguation which greatly increase the reliability of the copy number variant calling, which is vital for the detection of ultra rapid metabolizers.
We are currently investigating a multi-modal approach that can use the strengths of both technologies, as we would benefit from methodologies that can capture PGx-variants in a diverse sample whilst also providing highly accurate measures of copy number and structural variants.
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