Target Trial Emulation and Bias Through Missing Eligibility Data: An Application to a Study of Palivizumab for the Prevention of Hospitalization due to Infant Respiratory Illness

Target trial emulation (TTE) applies the principles of randomised controlled trials to the causal analysis of observational datasets. On challenge that is rarely considered in TTE is the sources of bias that may arise if the variables involved in the definition of eligibility into the trial are missing. We highlight patterns of bias that might arise when estimating the causal effect of a point exposure when restricting the target trial (TT) to individuals with complete eligibility data. Simulations consider realistic scenarios where the variables affecting eligibility modify the causal effect of the exposure and are Missing at Random (MAR) or Missing Not at Random (MNAR). We discuss multiple means to address these patterns of bias, namely, (i) controlling for the collider bias induced by the missing dataon eligibility, and (ii) imputing the missing values of the eligibility variables prior to selection into the TT. Results are compared to when TTE is performed ignoring the impact of missing eligibility. A study of Palivizumab, a monoclonal antibody recommended for the prevention of respiratory hospital admissions due to Respiratory Synctial Virus in high risk infants, is used for illustrations

Socioeconomic position, bronchiolitis and asthma in children:counterfactual disparity measures from a national birth cohort study

BACKGROUND: The debated link between severe respiratory syncytial virus (RSV) infection in early life and asthma has yet to be investigated within a social inequity lens. We estimated the magnitude of socioeconomic disparity in childhood asthma which would remain if no child were admitted to hospital for bronchiolitis, commonly due to RSV, during infancy. METHODS: The cohort, constructed from national administrative health datasets, comprised 83853 children born in Scotland between 1 January 2007 and 31 June 2008. Scottish Index for Multiple Deprivation (SIMD) was used to capture socioeconomic position. Emergency admissions for bronchiolitis before age 1 year were identified from hospital records. Yearly indicators of asthma/wheeze from ages 2 to 9 years were created using dispensing data and hospital admission records. RESULTS: Using latent class growth analysis, we identified four trajectories of asthma/wheeze: early-transient (2.2% of the cohort), early-persistent (2.0%), intermediate-onset (1.8%) and no asthma/wheeze (94.0%). The estimated marginal risks of chronic asthma (combining early-persistent and intermediate-onset groups) varied by SIMD, with risk differences for the medium and high deprivation groups, relative to the low deprivation group, of 7.0% (95% confidence interval: 3.7-10.3) and 13.0% (9.6-16.4), respectively. Using counterfactual disparity measures, we estimated that the elimination of bronchiolitis requiring hospital admission could reduce these risk differences by 21.2% (4.9-37.5) and 17.9% (10.4-25.4), respectively. CONCLUSIONS: The majority of disparity in chronic asthma prevalence by deprivation level remains unexplained. Our paper offers a guide to using causal inference methods to study other plausible pathways to inequities in asthma using complex, linked administrative data

A comparison of child mortality from potentially preventable causes in England and Sweden using birth cohorts from linked administrative datasets

Introduction Child mortality is nearly twice as high in England as in Sweden. A comparison of mortality from potentially preventable causes could inform health system responses. This study focused on respiratory tract infection (RTI)-related deaths, amenable to healthcare interventions, and sudden unexpected deaths in infancy (SUDI), amenable to public health interventions. Objectives and Approach We developed nationally-representative birth cohorts of singleton live births in 2003-2012 using a hospital admissions database in England and the Medical Birth Register in Sweden. Children were followed-up from 31st day of life until their fifth birthday via linkage to hospital admission and mortality records. We compared child mortality using Cox proportional hazards models to estimate hazard ratios (HR) for England versus Sweden for RTI-related mortality at 31-364 days and 1-4 years, and for SUDI mortality at 31-364 days. Models were adjusted for birth characteristics (gestational age, birthweight, sex, congenital anomalies), and socio-economic factors (maternal age and socio-economic status). Results Of 3,928,483 children in England, there were 807 RTI-related deaths at 31-364 days (17% of all deaths in the age range), 691 deaths at 1-4 years (31%), and 1,166 SUDIs (24%) in England. Corresponding figures for 1,012,682 children in Sweden were 136 (18%), 118 (25%) and 189 (24%). Unadjusted HRs for RTI-related deaths in England versus Sweden were 1.50 (95% confidence interval: 1.25-1.80) at 31-364 days. Adjustment for birth characteristics reduced the HR to 1.16 (0.97-1.39), and for socio-economic factors to 1.11 (0.92-1.33). Corresponding figures for RTI-related mortality at 1-4 years were 1.58 (1.30-1.92), 1.32 (1.09-1.61) and 1.30 (1.07-1.59), respectively. Unadjusted HRs for SUDIs reduced from 1.59 (1.36-1.85) to 1.40 (1.20-1.63) after adjusting for birth characteristics, and to 1.19 (1.02-1.39) after adjusting for socio-economic factors. Conclusion/Implications Higher prevalence of adverse birth characteristics (such as prematurity, low birthweight, congenital anomalies) contributed to increased risks of RTI-related and SUDI mortality in England relative to Sweden. Therefore, preventive strategies should focus on maternal health and socio-economic circumstances before and during pregnancy to reduce RTI-related and SUDI mortality in England

Age-specific incidence of A/H1N1 2009 influenza infection in England from sequential antibody prevalence data using likelihood-based estimation.

Estimating the age-specific incidence of an emerging pathogen is essential for understanding its severity and transmission dynamics. This paper describes a statistical method that uses likelihoods to estimate incidence from sequential serological data. The method requires information on seroconversion intervals and allows integration of information on the temporal distribution of cases from clinical surveillance. Among a family of candidate incidences, a likelihood function is derived by reconstructing the change in seroprevalence from seroconversion following infection and comparing it with the observed sequence of positivity among the samples. This method is applied to derive the cumulative and weekly incidence of A/H1N1 pandemic influenza in England during the second wave using sera taken between September 2009 and February 2010 in four age groups (1-4, 5-14, 15-24, 25-44 years). The highest cumulative incidence was in 5-14 year olds (59%, 95% credible interval (CI): 52%, 68%) followed by 1-4 year olds (49%, 95% CI: 38%, 61%), rates 20 and 40 times higher respectively than estimated from clinical surveillance. The method provides a more accurate and continuous measure of incidence than achieved by comparing prevalence in samples grouped by time period

Primary-school recorded special educational needs in children born with major congenital anomalies in England: A population-based study using the Education and Child Health Insights from Linked Data database

Objectives We provide a national overview of survival to primary school and recorded special educational needs (SEN) provision among children with hospital identified major congenital anomalies (MCAs) born in England. We also report changes before and after government reform of SEN in 2014. Methods We created a cohort of 6,180,400 singleton children born in England between 1 September 2003 and 31 August 2013 using linked administrative health and education records (from the ‘ECHILD’ database). MCAs were identified using hospital admission and mortality records during infancy. We used at least one record of SEN in state-school records as a proxy for SEN provision. We quantified: survival to age 5 using Kaplan-Meier survival analysis; the prevalence of recorded SEN during primary school Years 1 to 6; and the difference in proportion of children with recorded SEN in Year 1 before and after the 2014 government SEN reforms. Results Children with any MCA had 5-year survival rates of 95.1% (95% confidence interval, CI, 95.0, 95.2), compared with 99.7% (95% CI 99.7, 99.7) among children without a MCA. 41.5% (75,202/181,328) of children with an MCA attending state-school between Year 1 and 6 had any recorded SEN compared with 25.6% (1,282,979/5,008,624) of children without a MCA. Of the 12 system-specific MCA subgroups, children with chromosomal, nervous system and eye anomalies had the largest prevalence of recorded SEN. The prevalence of recorded SEN decreased by 4.9% (95% CI -5.3, -4.4) for children with any MCA compared with a reduction of 4.3% (95% CI -4.4, -4.2) for children without a MCA, when comparing pupils in Year 1 before and after 2014. Conclusion Recorded SEN among children with hospital identified MCAs was markedly higher than for those without MCAs, however more than half had no recorded SEN. Our findings suggest government reform in 2014 reduced SEN provision for children with MCAs

Determinants of accident and emergency attendances and emergency admissions in infants: birth cohort study

BACKGROUND: There is limited understanding of the drivers of increasing infant accident and emergency (A&E) attendances and emergency hospital admissions across England. We examine variations in use of emergency hospital services among infants by local areas in England and investigate the extent to which infant and socio-economic factors explain these variations. METHODS: Birth cohort study using linked administrative Hospital Episode Statistics data in England. Singleton live births between 1-April-2012 and 31-March-2019 were followed up for 1 year; from 1-April-2013 (from the discharge date of their birth admission) until their first birthday, death or 31-March-2019. Mixed effects negative binomial models were used to calculate incidence rate ratios for A&E attendances and emergency admissions and mixed effects logistic regression models estimated odds ratio of conversion (the proportion of infants subsequently admitted after attending A&E). Models were adjusted for individual-level factors and included a random effect for local authority (LA). RESULTS: The cohort comprised 3,665,414 births in 150 English LAs. Rates of A&E attendances and emergency admissions were highest amongst: infants born < 32 weeks gestation; with presence of congenital anomaly; and to mothers < 20-years-old. Area-level deprivation was positively associated with A&E attendance rates, but not associated with conversion probability. A&E attendance rates were highest in the North East (916 per 1000 child-years, 95%CI: 911 to 921) and London (876 per 1000, 95%CI: 874 to 879), yet London had the lowest emergency admission rates (232 per 1000, 95%CI: 231 to 234) and conversion probability (25% vs 39% in South West). Adjusting for individual-level factors did not significantly affect variability in A&E attendance and emergency admission rates by local authority. CONCLUSIONS: Drivers of A&E attendances and emergency admissions include individual-level factors such being born premature, with congenital anomaly and from socio-economically disadvantaged young parent families. Support for such vulnerable infants and families should be provided alongside preventative health care in primary and community care settings. The impact of these services requires further investigation. Substantial geographical variations in rates were not explained by individual-level factors. This suggests more detailed understanding of local and underlying service-level factors would provide targets for further research on mechanisms and policy priority

Factors predicting amoxicillin prescribing in primary care among children: a cohort study

Background: Antibiotic prescribing during childhood contributes to antimicrobial resistance, which is a major public health concern. Antibiotics are most commonly prescribed to children for respiratory tract infections (RTI). / Aim: To identify factors associated with amoxicillin prescribing and RTI consultation attendance in primary care in young children. / Design and Setting: Cohort study in Bradford with data from pregnancy to age 24-months collected between 2007-2013, linked to electronic primary care and air pollution data. / Methods: We calculated amoxicillin prescribing rates/1,000 child-years, and fitted mixed-effects logistic regression models, with general practice (GP) surgery as the random effect, to establish risk factors for amoxicillin prescribing and RTI consultation during the first two years. / Results: Among 2,493 children, the amoxicillin prescribing rate was 710/1,000 child-years during the first year (95% CI: 677-744) and 780/1,000 (745-816) during the second year. Odds of amoxicillin prescribing during year one were higher for infants who were male (adjusted OR 1.4 (1.1-1.6)), socio-economically deprived (1.4 (1.0-1.9)), and with a Pakistani ethnic background (1.4 (1.1-1.9)). Odds of amoxicillin prescribing during the second year were higher for infants with a Pakistani ethnic background (1.5 (1.1-2.0)/1.6 (1.2-2.0)) and pre-/early-term infants (1.2 (1.0-1.5)). Additional risk factors included caesarean delivery, congenital anomalies, household overcrowding, birth season, and formal childcare attendance. GP surgery-level variation explained 7-9% of variation in amoxicillin prescribing. / Conclusions: Socio-economic status and ethnic background are strongly associated with amoxicillin prescribing and RTI consultations during childhood. Interventions reducing RTI spread in household and childcare settings may reduce antibiotic prescribing in primary care

Using administrative data to evaluate national policy impacts on child and maternal health: a research framework from the Maternal and Child Health Network (MatCHNet)

Reducing health inequalities by addressing the social circumstances in which children are conceived and raised is a societal priority. Early interventions are key to improving outcomes in childhood and long-term into adulthood. Across the UK nations, there is strong political commitment to invest in the early years. National policy interventions aim to tackle health inequalities and deliver health equity for all children. Evidence to determine the effectiveness of socio-structural policies on child health outcomes is especially pressing given the current social and economic challenges facing policy-makers and families with children. As an alternative to clinical trials or evaluating local interventions, we propose a research framework that supports evaluating the impact of whole country policies on child health outcomes. Three key research challenges must be addressed to enable such evaluations and improve policy for child health: (1) policy prioritisation, (2) identification of comparable data and (3) application of robust methods