Confounding-adjustment methods for the causal difference in medians

Background With continuous outcomes, the average causal effect is typically defined using a contrast of expected potential outcomes. However, in the presence of skewed outcome data, the expectation (population mean) may no longer be meaningful. In practice the typical approach is to continue defining the estimand this way or transform the outcome to obtain a more symmetric distribution, although neither approach may be entirely satisfactory. Alternatively the causal effect can be redefined as a contrast of median potential outcomes, yet discussion of confounding-adjustment methods to estimate the causal difference in medians is limited. In this study we described and compared confounding-adjustment methods to address this gap. Methods The methods considered were multivariable quantile regression, an inverse probability weighted (IPW) estimator, weighted quantile regression (another form of IPW) and two little-known implementations of g-computation for this problem. Methods were evaluated within a simulation study under varying degrees of skewness in the outcome and applied to an empirical study using data from the Longitudinal Study of Australian Children. Results Simulation results indicated the IPW estimator, weighted quantile regression and g-computation implementations minimised bias across all settings when the relevant models were correctly specified, with g-computation additionally minimising the variance. Multivariable quantile regression, which relies on a constant-effect assumption, consistently yielded biased results. Application to the empirical study illustrated the practical value of these methods. Conclusion The presented methods provide appealing avenues for estimating the causal difference in medians.Peer reviewe

Language and health-related quality of life outcomes of children early-detected with unilateral and mild bilateral hearing loss

IntroductionWe aimed to describe the language and health-related quality of life (HRQoL) outcomes of children early-identified with unilateral or mild bilateral permanent hearing loss. This was a cross-sectional community-based study of children with mild bilateral or unilateral permanent hearing loss (including unilateral auditory neuropathy spectrum disorder (ANSD)), drawn from a population-based databank in Victoria, Australia.MethodsEnrolment in this databank is independent of early intervention and amplification approaches. Language and caregiver-reported HRQoL outcomes are described by type and degree of loss at three timepoints across child development: at age 2 years (n = 255), 5–7 years (n = 173) and 9–12 years (n = 45).ResultsAcross all age groups, average language outcomes were poorer than population normative scores by between a half to two thirds of a standard deviation. Children with mild bilateral hearing loss demonstrated poorer average language outcomes than children with unilateral hearing loss, particularly at younger ages. Children with unilateral ANSD showed language outcomes comparable to their peers with unilateral profound hearing loss. Children had poorer HRQoL psychosocial scores compared to physical scores, without obvious patterns of outcomes linked to degree or type of hearing loss.DiscussionThis study demonstrates children with early-identified unilateral or mild bilateral hearing loss have average language and HRQoL outcomes poorer than population normative expectations from an early age. These outcomes are observed at later ages across childhood. These findings provide a contemporary description of language and quality of life outcomes for children identified but not targeted by universal newborn hearing screening and raise questions of how to provide better support for these populations of children and their families

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Table1_Language and health-related quality of life outcomes of children early-detected with unilateral and mild bilateral hearing loss.docx

IntroductionWe aimed to describe the language and health-related quality of life (HRQoL) outcomes of children early-identified with unilateral or mild bilateral permanent hearing loss. This was a cross-sectional community-based study of children with mild bilateral or unilateral permanent hearing loss (including unilateral auditory neuropathy spectrum disorder (ANSD)), drawn from a population-based databank in Victoria, Australia.MethodsEnrolment in this databank is independent of early intervention and amplification approaches. Language and caregiver-reported HRQoL outcomes are described by type and degree of loss at three timepoints across child development: at age 2 years (n = 255), 5–7 years (n = 173) and 9–12 years (n = 45).ResultsAcross all age groups, average language outcomes were poorer than population normative scores by between a half to two thirds of a standard deviation. Children with mild bilateral hearing loss demonstrated poorer average language outcomes than children with unilateral hearing loss, particularly at younger ages. Children with unilateral ANSD showed language outcomes comparable to their peers with unilateral profound hearing loss. Children had poorer HRQoL psychosocial scores compared to physical scores, without obvious patterns of outcomes linked to degree or type of hearing loss.DiscussionThis study demonstrates children with early-identified unilateral or mild bilateral hearing loss have average language and HRQoL outcomes poorer than population normative expectations from an early age. These outcomes are observed at later ages across childhood. These findings provide a contemporary description of language and quality of life outcomes for children identified but not targeted by universal newborn hearing screening and raise questions of how to provide better support for these populations of children and their families.</p

Table3_Emotional behavioral outcomes of children with unilateral and mild hearing loss.docx

BackgroundDeaf and hard-of hearing (DHH) children often experience emotional/behavioral difficulties. The impact of unilateral/mild hearing loss (HL) on children's emotion and behavior are unclear. We aimed to describe emotional/behavioral, health related quality-of-life (HRQoL) and parent psychological distress outcomes of school-age children with unilateral/mild HL, compared to children with moderate to profound HL, and in relation to population norms; and identify predictive factors of emotional/behavioral difficulties.MethodsData of 339 DHH children, 5–12 years, enrolled in the Victorian Childhood Hearing Longitudinal Databank (VicCHILD), which include demographics, early development, medical/audiological characteristics and parent rated questionnaires of emotion/behavior, HRQoL and parental psychological distress collected at various stages of child's life were analyzed. We used Cohen's d to investigate the outcomes by measuring the mean score differences of both groups with published norms and logistic regression to analyze the factors predictive of emotional/behavioral difficulties.ResultsThe proportion of children with unilateral/mild HL and moderate to profound HL who experienced emotional/behavioral difficulties was similar (18.3% vs. 20.6%), with hyperactivity and poor prosocial behavior reported as the predominant symptoms in both groups. Mean emotional/behavioral scores of both groups were comparable and substantially higher than normative population scores. This was also the case for HRQoL and levels of parent distress. Among children with unilateral/mild HL, additional health needs were the strongest predictive factor, demonstrating an approximately 1.7-fold increase in odds of emotional/behavioral difficulties (OR = 1.67; 95% CI 1.29–2.17, p ConclusionChildren with unilateral/mild HL were just as likely as those with moderate to profound HL to experience more emotional/behavioral difficulties, poorer HRQoL and higher parental distress scores compared to population norms. Our findings justify the provision of early intervention, support and medical services for all DHH children to identify those at risk of poorer outcomes.</p

Table4_Emotional behavioral outcomes of children with unilateral and mild hearing loss.docx

BackgroundDeaf and hard-of hearing (DHH) children often experience emotional/behavioral difficulties. The impact of unilateral/mild hearing loss (HL) on children's emotion and behavior are unclear. We aimed to describe emotional/behavioral, health related quality-of-life (HRQoL) and parent psychological distress outcomes of school-age children with unilateral/mild HL, compared to children with moderate to profound HL, and in relation to population norms; and identify predictive factors of emotional/behavioral difficulties.MethodsData of 339 DHH children, 5–12 years, enrolled in the Victorian Childhood Hearing Longitudinal Databank (VicCHILD), which include demographics, early development, medical/audiological characteristics and parent rated questionnaires of emotion/behavior, HRQoL and parental psychological distress collected at various stages of child's life were analyzed. We used Cohen's d to investigate the outcomes by measuring the mean score differences of both groups with published norms and logistic regression to analyze the factors predictive of emotional/behavioral difficulties.ResultsThe proportion of children with unilateral/mild HL and moderate to profound HL who experienced emotional/behavioral difficulties was similar (18.3% vs. 20.6%), with hyperactivity and poor prosocial behavior reported as the predominant symptoms in both groups. Mean emotional/behavioral scores of both groups were comparable and substantially higher than normative population scores. This was also the case for HRQoL and levels of parent distress. Among children with unilateral/mild HL, additional health needs were the strongest predictive factor, demonstrating an approximately 1.7-fold increase in odds of emotional/behavioral difficulties (OR = 1.67; 95% CI 1.29–2.17, p ConclusionChildren with unilateral/mild HL were just as likely as those with moderate to profound HL to experience more emotional/behavioral difficulties, poorer HRQoL and higher parental distress scores compared to population norms. Our findings justify the provision of early intervention, support and medical services for all DHH children to identify those at risk of poorer outcomes.</p

Table1_Emotional behavioral outcomes of children with unilateral and mild hearing loss.docx

BackgroundDeaf and hard-of hearing (DHH) children often experience emotional/behavioral difficulties. The impact of unilateral/mild hearing loss (HL) on children's emotion and behavior are unclear. We aimed to describe emotional/behavioral, health related quality-of-life (HRQoL) and parent psychological distress outcomes of school-age children with unilateral/mild HL, compared to children with moderate to profound HL, and in relation to population norms; and identify predictive factors of emotional/behavioral difficulties.MethodsData of 339 DHH children, 5–12 years, enrolled in the Victorian Childhood Hearing Longitudinal Databank (VicCHILD), which include demographics, early development, medical/audiological characteristics and parent rated questionnaires of emotion/behavior, HRQoL and parental psychological distress collected at various stages of child's life were analyzed. We used Cohen's d to investigate the outcomes by measuring the mean score differences of both groups with published norms and logistic regression to analyze the factors predictive of emotional/behavioral difficulties.ResultsThe proportion of children with unilateral/mild HL and moderate to profound HL who experienced emotional/behavioral difficulties was similar (18.3% vs. 20.6%), with hyperactivity and poor prosocial behavior reported as the predominant symptoms in both groups. Mean emotional/behavioral scores of both groups were comparable and substantially higher than normative population scores. This was also the case for HRQoL and levels of parent distress. Among children with unilateral/mild HL, additional health needs were the strongest predictive factor, demonstrating an approximately 1.7-fold increase in odds of emotional/behavioral difficulties (OR = 1.67; 95% CI 1.29–2.17, p ConclusionChildren with unilateral/mild HL were just as likely as those with moderate to profound HL to experience more emotional/behavioral difficulties, poorer HRQoL and higher parental distress scores compared to population norms. Our findings justify the provision of early intervention, support and medical services for all DHH children to identify those at risk of poorer outcomes.</p